NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Montmayeur JP, le Coutre J, editors. Fat Detection: Taste, Texture, and Post Ingestive Effects. Boca Raton (FL): CRC Press/Taylor & Francis; 2010.

Cover of Fat Detection

Fat Detection: Taste, Texture, and Post Ingestive Effects.

Show details

Chapter 20Hypothalamic Fatty Acid Sensing in the Normal and Disease States

, , and .


Obesity, which encompasses the accumulation of excess fat in peripheral tissues and its associated health risks, is increasingly prevalent worldwide and has reached epidemic proportions. With over 1.1 billion overweight [body mass index (BMI) exceeding 25] and 312 million obese (BMI exceeding 30) adults worldwide, the rates of obesity have effectively tripled in the developing world, thanks to the increasingly popular Western lifestyle which generally involves the abundant consumption of energy-dense food and decreased physical activity (Hossain et al., 2007). The latent health risks associated with obesity are potentially devastating—in addition to metabolic disease, being obese increases the risk of type 2 diabetes (T2D), cardiovascular disease (CVD), and even various cancers (Calle and Kaaks, 2004).

Despite the undeniable influence of genetic and environmental factors, obesity is ultimately a resultant of, and perpetuated by, a disruption in energy homeostasis, whereby energy (food) intake exceeds energy expenditure. Normally, there is a series of concerted physiological and biochemical checks and balances initiated to handle acute, day-to-day fluctuations in energy balance: for example, an elevation in adiposity resulting from increased energy intake leads to counter-regulation via an increase in adipose-derived hormones, such as lesptin (Friedman, 2003), and an increase in energy expenditure (López et al., 2007). Conversely, the fasting state shifts the energy balance such that energy stores are maintained while an increased propensity for food intake results (Lelliott and Vidal-Puig, 2004). As a result of these feedback signals that relay changes in energy status, the caloric storage/body weight is generally stable for most humans over long periods of time despite the wide variations in day-to-day food intake that occur. These above homeostatic responses are poised to handle subthreshold fluctuations in food intake, but clearly, chronic hyper-caloric excess combined with reduced energy mobilization (i.e., exercise) limits their effectiveness (López et al., 2007), and leads to increased adiposity. In addition, this physiological cross-regulation also provides a reason for the inherent difficulty in losing large amounts of weight and sustaining that weight loss, as massive weight loss is capable of triggering rebound hunger (Friedman, 2003). Further impacting the effectiveness of the energy balance mechanism is the influence of the inherent sensory circuitry that mediates the pleasure and reward on feeding (Flier, 2004). Thus, identifying the nature of the satiety and hunger signals generated in the body that are involved in the regulation of feeding behavior has historically been a necessary preoccupation in obesity research.

By the mid-twentieth century, the glucostatic (Mayer, 1953) and lipostatic (Kennedy, 1953) hypotheses, which proposed that circulating nutrients (glucose and lipids, respectively) generated in amounts proportional to peripheral storage depots serve as signals to the brain in order to mediate alterations in energy intake and expenditure, were in place. As a result, research then shifted to focus on the primary energy storage sites in the periphery, including the adipose tissue, skeletal muscle, and the liver, and their potential ability to sense energy and mediate the control of energy intake. The liver, given that it is exposed to the postabsorption nutrient flow (Langhans, 1996) and that hepatocytes are essentially able to metabolize all fuels (Seifter and Englard, 1988), was a natural target that in particular was quite convincingly demonstrated as a possible mediator of the hunger/satiety signal (Langhans, 1996).

However, the hypothalamus in particular has long been championed as a key mediator of whole body energy homeostasis. Presently, it is generally accepted that it is involved in the day-to-day regulation of a number of factors including body temperature, blood pressure, thirst, and hunger, and is a vital structure for the integration of the nervous and endocrine systems. The first demonstrations of the hypothalamus serving as a satiety centre were conducted several decades ago, wherein hyperphagia and obesity resulted after the ventromedial nucleus of the hypothalamus was subjected to bilateral lesions (Hetherington and Ranson, 1942). Furthermore, the observed hyperphagia following the administration of the classical 2-deoxyglucose (2-DG) antime-tabolite into the third ventricle of the brain (Miselis and Epstein, 1975) demonstrated a central fuel-sensing component to the regulation of energy homeostasis.

Numerous landmark studies—the vast majority of which were conducted in the past decade—have demonstrated that the latter possibility holds much promise. The central nervous system (CNS) has been shown to sense hormones and nutrients in order to regulate not only food intake (Cota et al., 2006; Lam et al., 2008; Luheshi et al., 1999; Morton et al., 2006; Turton et al., 1996; Wolfgang and Lane, 2006) but also glucose homeostasis (Bence et al., 2006; Coppari et al., 2005; Gelling et al., 2006; Inoue et al., 2006; Kievit et al., 2006; Lam et al., 2005a,b,c; Obici et al., 2002a,b 2003). Of particular interest and relevance, changes in hypothalamic fatty acid levels and metabolism have been shown to regulate both food intake (Loftus et al., 2000) and glucose homeostasis (Obici et al., 2002a, 2003). As obesity and diabetes are characterized by hyperphagia and hyperglycemia, the characterization of defects in the hormone- and nutrient-sensing pathways in the hypothalamus that regulate energy and glucose homeostasis will shed light on the central component that initiates and perpetuates these metabolic diseases.

In order to gain a full appreciation of the physiologic control of nutrient input and output that is mediated by the brain, a closer look at the key molecular and enzymatic targets of the hypothalamus and their regulation is an absolute must.


Within the CNS, the hypothalamus appears to be the primary processor of peripheral signals—theoretically mechanical, neural, hormonal, or metabolic in nature—which indicate nutrient availability (Horvath et al., 2004). In terms of its composition, the hypothalamus comprises a set of anatomically distinct nuclei that are interconnected via axonal projections (López et al., 2007). These nuclei are equipped to respond to acute alterations in energy status by governing the expression of specific, homeostasis-relevant neuropeptides and neurotransmitters. The ventromedial hypothalamic nucleus (VMH) in particular has long been perceived as a “satiety centre,” due to the aforementioned finding that bilateral lesions in the VMH result in pronounced hyperphagia and obesity (Hetherington and Ranson, 1942). However, the molecular mechanisms underlying the feeding control by the VMH have, to date, yet to be satisfactorily tackled.

Based on the rather remarkable experimental findings of the recent past, the arcuate nucleus (ARC) has appeared to emerge as the “master” nuclei for the regulation of energy and glucose homeostasis. From an anatomical perspective, it can be seen why, situated around the base of the brain’s third ventricle, the ARC lies immediately above the median eminence where the capillary endothelium lacks tight junctions (Williams et al., 2001), effectively forming an incomplete blood–brain barrier (BBB); thus it is more conducive to allowing larger proteins and hormones to readily access the ARC neurons from circulation.

There are at least two distinct neuronal subtypes in the ARC that are able to process peripheral metabolic and feeding signals (Figure 20.1). The first are neurons that express the anorexigenic products of the peptide proopiomelanocortin (POMC). POMC is posttranslationally cleaved to a series of smaller peptides, the most notable of which are adrenocorticotropic hormone (ACTH) and α-melanocyte stimulating hormone (α-MSH), the latter of which exerts a net catabolic action that is important in the stimulation of feeding (Seeley and Woods, 2003). Once released, α-MSH carries out its theorized anorexigenic action by binding the MC4 receptor (MC4R), one of five known melanocortin receptors (MCRs) (Seeley and Woods, 2003), in downstream effector neurons. Belonging to the second subtype are neurons that coexpress the orexigenic peptides neuropeptide Y (NPY) and agouti-related peptide (AgRP). The activation of these orexigenic neurons leads to the inhibition of anorexigenic signaling in two ways: (1) AgRP/NPY neurons synapse directly with POMC neurons, providing an inhibitory tone and (2) AgRP itself is an inverse agonist at MC4Rs, effectively antagonizing the effects of α-MSH. Both the AgRP/NPY and POMC neurons (“first-order” neurons) have axonal projections to other hypothalamic nuclei (housing downstream “second-order” neurons) as well: the AgRP/NPY neurons project primarily to the paraventricular nucleus (PVN), while POMC neurons project more broadly, reaching other nuclei such as the lateral hypothalamus (LH) in addition to the PVN (López et al., 2007). Collectively, the interplay between these orexigenic and anorexigenic neuronal subsets and their downstream effector signaling form the melanocortin signaling system (Figure 20.1); it is the activation of this so-called hypothalamic melanocortin tone (Cone, 2005) that is thought to be instrumental in the regulation of homeostasis.

FIGURE 20.1. The hypothalamic melanocortin system and the regulation of energy and glucose homeostasis.


The hypothalamic melanocortin system and the regulation of energy and glucose homeostasis. The hypothalamic ARC is a critical mediator of energy and glucose homeostasis. Two groups of ARC neurons (“first-order” neurons), the NPY and AgRP (more...)

Numerous studies have shown the role of these neurons’ activity in the regulation of energy balance and glucose homeostasis. Central NPY injections, which have been previously shown to potently stimulate feeding within minutes (Clark et al., 1985), were recently shown to markedly diminish the ability of a hyperinsulinemic clamp to lower glucose production (GP) (van den Hoek et al., 2004). Interestingly, rates of peripheral glucose disposal and lipolysis were unaffected in the NPY-treated group (van den Hoek et al., 2004). Overall, the data suggests that NPY release must be downregulated in order for insulin to suppress hepatic GP, and that an increase in NPY secretion can lead to insulin resistance. In the case of AgRP, ubiquitous expression of human AgRP in transgenic mice caused obesity, while in a similar vein, AgRP was found to have an eightfold increase in expression in the leptin-deficient ob/ob mice (Ollmann et al., 1997). As for the importance of melanocortin signaling, van Dijk and colleagues demonstrated that relative to vehicle-treated controls, the third intracerebroventricular (i.c.v.) administration of the MCR antagonist SHU9119 to rats doubled not only water but also food intake, resulting in increased body weight (Adage et al., 2001). When other metabolic parameters were assessed, there was increased fat and glycogen content, and elevated plasma cholesterol, leptin, insulin in i.c.v. SHU9119-treated animals (Adage et al., 2001).

The hypothalamic melanocortin signaling system is also heavily regulated by circulating hormones. AgRP/NPY neurons are inhibited by both leptin and insulin (Schwartz et al., 2000) while conversely, POMC neurons are stimulated by input from leptin (Cowley et al., 2001) and insulin (Plum et al., 2006). The administration of i.c.v. insulin increases the expression of POMC mRNA, and reduces food intake; however, the latter anorexic effects were prevented with a subthreshold dose of SHU9119 (Benoit et al., 2002). Furthermore, while it had been shown that hypothalamic insulin signaling is required for the suppression of hepatic GP (Obici et al., 2002b), Jens Brüning and colleagues recently revealed with the use of AgRP neuron-specific insulin receptor (IR) knockout mice that insulin action in AgRP-expressing neurons is required for this GP suppression (Konner et al., 2007).

Overall, it is apparent that key neurons in the hypothalamus, most likely in the ARC, are poised to integrate a variety of hormonal and metabolic signals in order to interpret the state of energy balance and in turn, mediate the necessary metabolic and behavioral responses in order to compensate for deviations from homeostasis. But in particular, this review will focus on the recently determined ability of hypothalamic fatty acid metabolism to regulate homeostatic mechanisms.


The brain is heavily reliant on the oxidation of glucose to meet its significant energy demands. And while the brain does not, to our knowledge, use fatty acids as a primary source of energy, it has been demonstrated recently that select enzymes and intermediates of fatty acid metabolism contribute to the hypothalamus’ ability to serve as a monitor of energy status. In 2002, Rossetti and colleagues were the first to demonstrate that the central administration of long-chain fatty acids (LCFAs) triggered a hypothalamic response to regulate energy as well as glucose homeostasis.

Specifically, the administration of oleic acid (a type of LCFA) centrally into the third cerebral ventricle (i.c.v.) of rodents was shown to produce a modest yet significant decrease in plasma insulin and glucose levels within 4 h of the infusion (Obici et al., 2002a,b). This indicates that i.c.v. oleic acid may have enhanced insulin sensitivity, and to better assess this, the effects of central oleic acid infusion were coupled to a pancreatic-euglycemic clamp protocol. The infusion of i.c.v. oleic acids for 6 h did indeed result in a reduction in hepatic GP under clamped, basal insulin conditions, indicating an enhancement in insulin sensitivity; interestingly, the infusion of the medium-chain fatty acid octanoic acid did not yield the same results, revealing specificity in the nature of the hypothalamic signal (Obici et al., 2002a,b). The coadministration of a KATP channel blocker, the sulfonylurea glybenclamide, with the i.c.v. oleic acid was able to nullify the insulin-sensitizing effect of i.c.v. oleic acid alone (Obici et al., 2002a,b). Thus, as seen with insulin and leptin (Spanswick et al., 1997, 2000), LCFAs appear to activate hypothalamic neurons via a KATP channel-dependent mechanism. Furthermore, this was in line with a later finding demonstrating that alterations in hypothalamic KATP channel activity per se can regulate GP (Pocai et al., 2005).

The same study looked at the effects of an acute increase in central LCFAs with respect to the regulation of energy balance, namely food intake. Following a bolus administration 1 h prior to the dark cycle, i.c.v oleic acid-treated rats had decreased food intake—the effects of which, remarkably, lasted for 2 days; this is likely mediated by the fact that i.c.v. oleic acid decreased the hypothalamic NPY mRNA levels versus vehicle-injected control rodents (Obici et al., 2002a,b).

Thus, the LCFA oleic acid serves as a central signal of surfeit/nutrient abundance, which in turn triggers the series of neuronal signaling cascades necessary to regulate nutrient intake and production. But how effective is this signal in models of obesity and/or diabetes? In a follow-up study, the same group evaluated whether short-term changes in nutrient availability can affect the ability of central oleic acid to regulate energy and glucose homeostasis. In rats fed a highly palatable, high-fat diet for 3 days (~140 kcal/day), the bolus administration of i.c.v. oleic acid was unable to recapitulate the significant decrease in food intake observed over 2 days in rodents fed a standard chow (Morgan et al., 2004). As for a possible underlying mechanism, the loss in the anorexigenic signal initiated by i.c.v. oleic acid in hyperphagic rats may be due to an incomplete inhibition of the orexigenic NPY expression: i.c.v oleic acid was only able to inhibit hypothalamic NPY expression in hyperphagic rats to 50% of the levels that were seen in standard chow-fed rodents (Morgan et al., 2004). In a similar vein, i.c.v oleic acid was able to inhibit the hypothalamic expression of the orexigenic AgRP by 75%, but this inhibition was lost in the high-fat diet fed, hyperphagic rodents (Morgan et al., 2004). With regard to the effect of central oleic acid on insulin action, the ability of i.c.v. oleic acid to suppress GP under conditions of a pancreatic-euglycemic clamp was nullified in rodents that had received the high-fat diet for 3 days; interestingly, by limiting the high-fat diet caloric intake to ~80 and ~55 kcal/day (versus ~140 kcal/day seen in hyperphagia), the ability of i.c.v. oleic acid to suppress hepatic GP was progressively restored (Morgan et al., 2004). This provides compelling evidence that the hypothalamic responses triggered by an acute increase in central LCFAs are nutritionally regulated, and presents a startling reality in terms of how rapidly intrinsic homeostatic mechanisms can fail.

Circulating fatty acids can readily access the brain, where they equilibrate with neuronal long-chain fatty acyl-CoAs (LCFA-CoAs) (Miller et al., 1987). Illustrating that circulating plasma fatty acids can access the brain and recapitulate the effect of directly administered i.c.v. oleic acid on glucose homeostasis would undoubtedly further the physiological relevance of this finding. Rossetti and colleagues designed a series of elegant experiments to look at this in greater detail. When lipids were infused intravenously for 4 h to induce hyperlipidemia, glucose uptake and GP were unaffected during a pancreatic-euglycemic clamp; however, when an i.c.v. infusion of the KATP channel blocker glybenclamide was administered during the lipid infusion, there was a significant elevation (50%) in GP, which was attributed to an increase in glycogenolysis (Lam et al., 2005b). As i.c.v. glybenclamide alone had no effect on GP in the absence of the intravenous lipid infusion (Lam et al., 2005b), this demonstrates that circulating lipids lower hepatic GP via a hypothalamic KATP channel-dependent mechanism, which is in line with the requirements of the i.c.v.-administered oleic acid to regulate GP (Obici et al., 2002a,b). The results of these pharmacological findings were confirmed with a genetic approach, in which the ability to restrain GP in the presence of increased lipid availability was lost in mice deficient in the KATP channel subunit Sur1 (Lam et al., 2005b). Once LCFAs gain access to the brain, they are esterified to LCFA-CoAs by the enzyme long-chain acyl-CoA synthetase (ACS), the activity of which can be pharmacologically inhibited by triacsin C. The bilateral infusion of triacsin C into the mediobasal hypothalamus was able to disrupt the hepatic autoregulation of GP in response to lipid infusion (Lam et al., 2005b), much like what was seen with the use of glybenclamide. This demonstrates that the generation of LCFA-CoAs from LCFAs selectively in the mediobasal hypothalamus—triacsin C infusions into the PVN failed to reproduce the effect (Lam et al., 2005b)—is necessary in the generation of the central signal to regulate glucose homeostasis. In the final part of the study, the authors investigated the descending pathway responsible for carrying out the hypothalamic effect of circulating LCFAs on GP. In rats that underwent the hepatic branch vagotomy, a procedure in which the hepatic branch of the vagus nerve is surgically transected, lipid infusions resulted in an increase in GP; the glucose kinetic parameters were unaffected in the sham-operated control group (Lam et al., 2005b). Taken together, the study illustrates that circulating LCFAs can regulate GP via a hypothalamically triggered mechanism that is dependent on (1) the esterification of LCFAs to LCFA-CoAs, (2) functional KATP channels, and (3) neural transmission via the vagus nerve.

At this point, the studies convincingly demonstrated the importance of the hypothalamic LCFA signal in regulating energy and glucose homeostasis, but the importance of fatty acid oxidation in this signal remained unclear. Carnitine palmitoyltransferase-1 (CPT1) regulates the transportation of LCFAs into the mitochondria, where they undergo β-oxidation (Figure 20.2), and its activity is likely a key determinant in the level of cytosolic pool of LCFAs. Based on the observation that i.c.v. oleic acid but not octanoic acid, a medium-chain fatty acid which does not require CPT1 for mitochondrial entry (Obici et al., 2002a,b), has suppressive effects on food intake and GP, Rossetti and colleagues then tested if CPT1 activity-mediated changes in cytosolic LCFAs can recapitulate the observed effects with i.c.v.-administered LCFAs. Specifically, the study made use of molecular and pharmacological approaches to inhibit CPT1 with the use of a ribozyme designed to cleave the “CPT1A” (predominant hypothalamic isoform) mRNA and CPT1-specific inhibitors, respectively (Obici et al., 2003). Before assessing the physiological effect of CPT1 inhibition, molecular analyses were conducted, and it was determined that i.c.v. delivery of the ribozyme did indeed substantially decrease “CPT1A” mRNA, and that i.c.v. ribozyme as well as the pharmacological inhibitors resulted in a marked decrease in CPT1 activity, both resulting in an increase in the concentration of LCFA-CoAs (Obici et al., 2003). Feeding behavior was then assessed as per previous studies (Obici et al., 2002a,b), and it was determined that i.c.v. injection of the CPT1 ribozyme as well as the pharmacological inhibitors were all able to produce a marked reduction in food intake for 48 h versus the i.c.v. infusions of the control ribozyme or the inactive stereoisomer of the CPT1 inhibitor (Obici et al., 2003). Once again, this was the result of a down-regulation in mRNA of both the orexigenic neuropeptides AgRP and NPY (Obici et al., 2003). In terms of the effects of central CPT1 inhibition on whole body insulin action, it was found that the i.c.v. administration of the CPT1 ribozyme (3 days before pancreatic-euglycemic clamp) or CPT1 inhibitor (concurrent infusion) resulted in a substantial and significant decrease in GP (Obici et al., 2003). Based on the results, it can be concluded that the inhibition of hypothalamic CPT1 activity, and the resultant increase in hypothalamic LCFA-CoA levels, was sufficient to produce a surfeit signal to suppress food intake as well as GP (Obici et al., 2003).

FIGURE 20.2. Generation of the hypothalamic LCFA-CoA surfeit signal.


Generation of the hypothalamic LCFA-CoA surfeit signal. LCFA-CoAs gain access to the mitochondria to undergo β-oxidation via the acyltransferase CPT1, which is located on the outer mitochondrial membrane. Cellular fat oxidation is regulated by (more...)

In a parallel finding, M. Daniel Lane’s group showed that mice that were deficient in CPT1c, a recently discovered CNS-specific isoform of CPT1 that is expressed in high amounts in the hypothalamus in addition to CPT1a (Price et al., 2002), weighed significantly less than their wildtype littermates at the end of a 15-week period and consumed less food after a fast (Wolfgang et al., 2006). However, despite the homology to the established CPT1a and CPT1b isoforms, CPT1c was found in vitro to lack the ability to catalyze the acyl transfer from LCFAs to carnitine, which CPT1a and CPT1 are capable of (Wolfgang et al., 2006). Thus, it is likely that CPT1c’s role in energy balance is independent of the altered β-oxidation mechanism that has been set forth by Rossetti’s group. Indeed, in a follow-up study, it was determined that CPT1c knockout mice exhibited similar levels of hypothalamic LCFA-CoAs as their wildtype littermates, either in the fasted or fed state (Wolfgang et al., 2008). Thus, further work needs to be completed in order to identify the nature of the metabolite or intermediate that is necessary in generating the CPT1c-mediated hypothalamic surfeit signal.

Now that the hypothalamic lipid-sensing mechanism is in place, it is time to make a return to the effectiveness of this surfeit signal in the obese state. Recall that short-term (3 day) overfeeding on a highly palatable, high-fat diet was able to negate the ability of central oleic acids to regulate food intake and GP (Morgan et al., 2004). Rossetti’s group asked if defective lipid-sensing mechanisms in the hypothalamus are partly responsible for this negation, and in particular, they focused on the role of CPT1 activity. As the rise in LCFA-CoAs is a critical initiator of this signal, the authors specifically postulated that, in the overfed model, the increase in lipid availability fails to translate into this increase in the intracellular pool of LCFA-CoA (Pocai et al., 2006). This was indeed the case: when rats fed a standard chow were administered a systemic lipid emulsion designed to double plasma LCFAs, this resulted in a doubling in hypothalamic LCFA-CoAs as previously seen (Lam et al., 2005a–c); however, in the overfed rats, this increase in circulating lipids failed to increase hypothalamic LCFA-CoAs (Pocai et al., 2006). The lack of hypothalamic LCFA-CoA increase in overfed rats was also seen when oleic acid was directly infused into the hypothalamus (Pocai et al., 2006), thus confirming that in overfed rats central oleic acids lack the metabolic and anorectic effects, and that the failure to increase hypothalamic LCFA-CoAs was not likely due to impeded BBB LCFA transport. A possible explanation for the observed effects is that there might be an enhanced rate of LCFA-CoA metabolism in the hypothalamus; indeed, hypothalamic CPT1 activity was significantly increased in the overfed rats (Pocai et al., 2006). Remarkably, by hypothalamically administering a CPT1a inhibitor or ribozyme to suppress CPT1a activity or expression, respectively, the authors were able to suppress food intake as well as GP in overfed rodents (Pocai et al., 2006). Thus, inhibiting hypothalamic lipid oxidation via the inhibition of the CPT1 activity is sufficient to restore energy balance as well as glucose homeostasis in overfed rodents.

Taken together, these noteworthy studies highlight the importance of central fatty acid metabolism in initiating the hypothalamic behavioral and metabolic responses necessary to regulate energy and glucose homeostasis. Thus, it is important to acquire an understanding of the upstream biochemical processes that are involved in the formation of LCFA-CoAs, as they are all ultimately responsible for the generation of this hypothalamic surfeit signal.


The access of circulating LCFAs to the CNS is proportional to the plasma fatty acid concentration, and once in neuronal cells, they are rapidly esterified by ACSs to form LCFA-CoAs (Lam et al., 2005c). Yet, this is not the sole way that LCFA-CoAs can be generated in the brain (Figure 20.2). In fact, LCFA-CoAs can also be made de novo with the aid of upstream biosynthetic enzymes and metabolite intermediates (Wakil et al., 1983).

As described earlier, LCFA-CoAs gain access to the mitochondria to undergo β-oxidation via the acyltransferase CPT1, which is located on the outer mitochondrial membrane. The two most well-characterized isoforms of CPT1 are CPT1a (the liver isoform) and CPT1b (the muscle isoform), and the former is most predominant in the brain. Cellular fat oxidation is regulated by the availability of malonyl-CoA, which binds CPT1 and potently inhibits its activity. Malonyl-CoA, in turn, is mainly derived from acetyl-CoA—an end-product of glycolysis—via the enzyme acetyl-CoA carboxylase (ACC); thus, the pathway is in a prime position to accurately monitor cellular energy status (Lam et al., 2005c). Finally, ACC activity is allosterically inhibited by the adenosine monophosphate-activated protein kinase (AMPK)-mediated phosphorylation.

Collectively, these regulatory enzymes and metabolite intermediates of the fatty acid biosynthesis pathway are poised to be key players in triggering the hypothalamic response to regulate energy as well as glucose homeostasis, and there is ample evidence suggesting that this may be the case.

20.4.1. AMP-Activated Protein Kinase

AMPK is an evolutionarily conserved energy sensor that in essence acts as a fuel gauge of mammalian cells (Hardie and Carling, 1997). It is expressed in most tissues, including the hypothalamus (Stapleton et al., 1996), and has a vast array of functions systemically and, more recently identified to function, centrally. AMPK operates by phosphorylation of various targets and by responding to an increasing cellular AMP:ATP ratio.

AMPK in the periphery responds to a diverse range of hormonal, physiological, and pathological stimuli (Ramamurthy and Ronnett, 2006). Its activity is responsive to a large number of hormonal cues: leptin has been found to stimulate glucose uptake (Kamohara et al., 1997) and fatty acid oxidation (Minokoshi et al., 2002) in skeletal muscle by activation of AMPK while adiponectin stimulates glucose utilization and fatty-acid oxidation in muscle and liver also by activating AMPK (Yamauchi et al., 2002). In general, activation of AMPK by ATP-depleting cellular stresses switches on ATP-generating catabolic pathways while ATP-consuming processes, including parameters such as glucose homeostasis, lipid metabolism, and mitochondrial biogenesis (Kahn et al., 2005) are switched off.

The hypothalamus has been suggested as a central mediator of energy homeostasis. Recently, AMPK in the hypothalamus has been investigated for its role in this regulation. Under normal physiological conditions, AMPK activity increases during fasting and decreases upon refeeding (Minokoshi et al., 2004). Conversely, modulating AMPK activity per se changes feeding behavior. It has been shown that central administration of 5-amino-4-imidaszole carboxamide riboside (AICAR), a pharmacological activator of AMPK, can raise food intake in rodents (Andersson et al., 2004; Hu et al., 2005; Kim et al., 2004). Moreover, dominant negative AMPK expression in the hypothalamus decreases feeding and body weight whereas constitutively active hypothalamic AMPK expression promotes feeding and increases body weight (Minokoshi et al., 2004). These changes in feeding patterns are accompanied by changes in neuropeptide expressions. Particularly, under ad libitum fed conditions, hypothalamic dominant negative AMPK decreased NPY and agouti-related protein (AgRP) mRNA levels whereas constitutively active AMPK increased both under fasted conditions. The AMPK-induced NPY fluctuation is suggested to be mediated by cAMP response element-binding protein (CREB) phosphorylation (Kim et al., 2004). In vitro studies with neuronal cell lines expressing AgRP are in support of these findings as high cellular ATP concentration decreased phosphorylation of AMPK and AgRP expression while low cellular ATP concentrations increased both (Lee et al., 2005).

As discussed earlier, energy regulation is largely based upon neuropeptide release from specific neuronal populations, namely the POMC and AgRP/NPY neurons in the ARC of the hypothalamus. The above findings would suggest that energy regulation signaling through AMPK selectively impacted AgRP/NPY neurons given that only the expression of orexigenic peptides AgRP and NPY, but not the anorexigenic peptide (POMC), was altered. However, recent genetic knockout models shed light on the possible involvement of both neuronal types. In particular, selective knockout of AMPK in either AgRP/NPY or POMC neurons in mice disrupted energy homeostasis, where the former exhibited an age-dependent lean phenotype and the latter developed obesity due to dysregulation in food intake and energy expenditure (Claret et al., 2007). These studies, along with the recent finding that an obesity-resistant hypophagic rat strain (Lou/C) exhibited impaired AMPK responses to starvation (Taleux et al., 2007), collectively established that AMPK signaling is necessary for proper energy balance.

Associated findings suggest that circulating nutrients, which are known to control energy balance, also change hypothalamic AMPK activity. Central administration of glucose significantly decreased AMPKα2 activity (Minokoshi et al., 2004). In support of this, central 2-deoxyglucose administration, which inhibited glucose utilization, activated hypothalamic AMPK activity (Kim et al., 2004). In addition, α-lipoic acid, a short-chain fatty acid that is a cofactor of mitochondrial enzymes with anorectic properties, also inhibited hypothalamic AMPK activity and was associated with decreased food intake and body weight (Kim et al., 2004). Further, as in the periphery, various hormonal signals involved in appetite control are able to modulate hypothalamic AMPK activity. Initial studies of leptin, an anorectic peptic hormone, administration peripherally found it to reduce hypothalamic AMPK activity (Andersson et al., 2004). Consistent with this, hypothalamic administration of either leptin or insulin also decreased hypothalamic AMPK activity (Andersson et al., 2004; Minokoshi et al., 2004). Interestingly, leptin’s alteration of AMPK activity was absent in a mouse model with melanocortin-4 (MC4) receptor knockout, indicating that the MCR signaling mediates leptin’s effect on AMPK activity (Minokoshi et al., 2004). Further, constitutively active AMPK expression in the hypothalamus blocked leptin’s anorectic effect, suggesting that leptin’s appetite regulation requires modulation of AMPK activity (Minokoshi et al., 2004). More recently, the acute effects of the important anorectic gut peptide, glucagon-like peptide 1 (GLP-1) has been found to be mediated, at least in part, by hypothalamic AMPK as the food intake lowering effect of i.c.v. GLP-1 is accompanied by reduction of hypothalamic AMPKα2 mRNA levels (Seo et al., 2008).

Contrary to anorectic peptides, orexigenic peptides such as ghrelin (Andersson etal., 2004; Kola et al., 2005), AgRP (Minokoshi et al., 2004), and orexigenic cannabinoids (Kola et al., 2005) stimulated hypothalamic AMPK activity. More recently, it was shown that the adipocyte-secreted hormone adiponectin also enhanced AMPK activity in the ARC to stimulate food intake and reduce energy expenditure (Kubota et al., 2007). To strengthen the point, it was previously identified in vitro that both insulin’s anorexigenic and ghrelin’s orexigenic alteration of NPY were only evident in the presence of glucocorticoids (Goto et al., 2006; Sato et al., 2005). More interestingly, it was recently identified that this glucocorticoid-induced increase in NPY was via AMPK signaling (Shimizu et al., 2008). Taken together, the discussed findings show that AMPK is a downstream enzyme that converges and coordinates various nutrient and hormonal signals, anorexigenic and orexigenic, in the hypothalamus to regulate energy homeostasis.

It is perhaps interesting to note that the pattern of neuropeptide regulation elicited by the manipulations of hypothalamic AMPK activity, i.e., changes in NPY/AgRP but not POMC levels (Minokoshi et al., 2004), is similar to that seen with central fatty acids administration (Obici et al., 2002a,b) or manipulation of hypothalamic lipid metabolism by inhibition of CPT1 (Obici et al., 2003). This hints at a possible parallel or converging mechanism at work bridging AMPK to fatty acid sensing in the brain. In fact, one of the best characterized targets of AMPK is the phosphorylation of ACC. AMPK negatively regulates ACC activity through phosphorylation (Munday et al., 1988; Sim and Hardie, 1988). This inhibition hinders the conversion of acetyl-CoA to malonyl-CoA, the latter of which is known to inhibit CPT1 action (McGarry et al., 1978). It is therefore reasonable to postulate that the effects of energy regulation elicited by AMPK are mediated by the downstream fatty acid sensing mechanism via the “malonyl-CoA → CPT1 inhibition → LCFA-CoA accumulation” hypothesis of appetite regulation. To compliment this hypothesis, it was found that the suppression of food intake by C75, a fatty acid synthase (FAS) inhibitor, is accompanied by decreased AMPK activity (Kim et al., 2004).

While the role of AMPK in facilitating nutrient and hormonal regulation of energy homeostasis is clear—with strong evidence pointing to its role in altering hypothalamic neuropeptide gene expression in specific neuronal populations, possibly involving the fatty acid metabolism pathway—the precise upstream mechanisms by which AMPK is phosphorylated and activated to exert its energy regulation is open to speculation. AMPK catalytic activity is triggered upon two conditions, namely the conformational change of the γ subunit of AMPK under sufficient AMP concentration and the phosphorylation of its α-subunit by an upstream AMPK kinase (AMPKK) that leads to consequent activation of AMPK. LKB1, the Peutz-Jeghers syndrome tumor suppressor gene is a known AMPKK (Hawley et al., 2003; Woods et al., 2003). However, while it is widely expressed in various tissues, LKB1’s role in brain AMPK activation remains largely unknown (Rowan et al., 2000; Ramamurthy and Ronnett, 2006). More recently, the calcium/calmodulin-dependent protein kinase β (CaMKK2) has also been identified as an AMPKK (Hawley et al., 2005; Hurley et al., 2005; Woods et al., 2005). In fact, CaMKK2 has now been shown to mediate hypothalamic AMPK activity to regulate production of NPY, and mice with CaMKK2 inhibition had decreased NPY and AgRP mRNA accompanying weight loss and inhibited appetite (Anderson et al., 2008).

20.4.2. Acetyl-CoA Carboxylase

Fatty acids that are present in the cells are either imported from the circulation or generated de novo. The committed step of de novo fatty acid biosynthesis is the initial conversion of acetyl-CoA to malonyl-CoA, which is mediated by the enzyme ACC (Wakil et al., 1983). There exists two isoforms of ACC, ACC1, and ACC2, both of which are present in the brain (Gao and Lane, 2003; Kim et al., 2002). It remains unclear, however, whether one or both isoforms in the hypothalamus are responsible for monitoring energy homeostasis. Using a mouse knockout model, it was first identified in mice lacking ACC2 that although these animals had 20%–30% higher food consumption in comparison to wildtype, their body weights were significantly lower than that of wildtype animals. Further, these ACC2 knockout mice were leaner, with less fat in their adipose tissues (Abu-Elheiga et al., 2001). The unmatched food intake and body weight might in part be accounted for by increased energy expenditure in ACC2 knockout mice (Choi et al., 2007). Unfortunately, as the aforementioned mice are whole body ACC2 knockouts with changes occurring in the periphery, one is unable to pinpoint from these two studies the precise contribution of hypothalamic ACC in the observed energy regulation changes. The advantages of knockout models in analyzing hypothalamic ACC comes to a halt at this stage given that global knockout of the ACC1 gene is embryonically lethal (Abu-Elheiga et al., 2005) and hypothalamic-specific ACC knockouts have not yet been reported (Wolfgang et al., 2006).

With this said, however, a few recent studies have highlighted the importance of hypothalamic ACC in energy balance through other pharmacological and molecular approaches. Of note, it was identified that ACC makes critical contributions to leptin’s inhibition of food intake (Gao et al., 2007). It was found in this study that i.c.v. leptin, which inhibits AMPK activity, activates ACC. The fact that constitutively active AMPK prevented ACC activation in response to i.c.v. leptin strengthens the claim that AMPK lies upstream of ACC’s energy regulatory effects. This is perhaps no surprise given that AMPK is a well-established inhibitor of ACC, as discussed in previous sections. Also of interest is the finding that blockage of ACC activity eliminated the anorectic effect of leptin and prevented the drop in NPY mRNA usually observed with i.c.v. leptin. In fact, such ACC blockade also abolished the iv leptin-induced rise in malonyl-CoA level, highlighting that the energy regulation of ACC is due to a rise in its product, malonyl-CoA (Gao et al., 2007). This, again, is in concordance with the LCFA-CoA energy homeostasis hypothesis, i.e., malonyl-CoA inhibits CPT1, increasing cytosolic LCFA-CoA levels. While most studies thus far have focused on energy homeostasis, a recent study pointed at ACC’s possible involvement in glucose homeostasis (Cesquini et al., 2008). Citrate, an intermediate metabolite produced in the mitochondria in the citric acid cycle, had previously been shown to promote satiety when administered into the hypothalamus (Roman et al., 2005). Given that citrate is an allosteric effector of ACC activity, the authors, upon confirming that ACC activity is significantly reduced by i.c.v. citrate, found that such administration not only decreased food intake and body weight, but also resulted in lower blood glucose levels during glucose tolerance test and increased glucose uptake during hyperglycemic–euglycemic clamp settings (Cesquini et al., 2008). Of note is the striking finding that the anorectic phenotype induced by ACC activation and subsequent malonyl-CoA formation can indeed be reversed by promoting the reverse reaction, namely, the conversion of malonyl-CoA back to acetyl-CoA by enzyme malonyl-CoA decarboxylase (MCD). It was found in a set of elegant molecular manipulation experiments that overexpressing MCD using adeno-associated viruses injected into the mediobasal hypothalamus of animals led to a rapid increase in food intake in such animals accompanied by a gradual development of obesity (He et al., 2006). Further, these MCD-overexpressing animals exhibited impaired suppression of GP during insulin-clamped settings (He et al., 2006). In accordance with the fatty acid sensing hypothesis, these MCD-overexpressed rats not only had a significant reduction in malonyl-CoA levels, but also a decrease in LCFA-CoA abundance. Notably, the LCFA-CoA levels in these animals are highly comparable to those seen in animals with pharmacological inhibition of LCFA esterification with triacsin-C in the mediobasal hypothalamus, which also exhibited impaired glucose homeostasis (Lam et al., 2005a–c).

20.4.3. Fatty Acid Synthase and the Malonyl-CoA Hypothesis

FAS catalyzes the synthesis of LCFA-CoAs from malonyl-CoA in a downstream reaction of the reductive synthesis of LCFAs. The potential role for fatty acid intermediates in the regulation of energy balance originally stemmed from findings revealing that the systemic as well as central treatment of mice with the FAS inhibitor cerulenin—a fungus-derived compound originally developed as an anticancer agent (López and Vidal-Puig, 2008)—led to the marked inhibition of feeding and subsequently, weight loss (Loftus et al., 2000). However, the authors believed that this agent may have toxic properties because of its epoxide structure, and synthesized a closely related compound termed C75 (Loftus et al., 2000), a FAS inhibitor that has since acquired immense popularity in studies investigating the physiological effects of the in vivo inhibition of fatty acid synthesis.

In the seminal paper by Kuhajda and colleagues, the physiological effect of inhibiting fatty acid synthesis on global lipid metabolism was initially assessed with a single intraperitoneal (i.p.) injection of C75, and the result in the treated mice was profound weight loss which was primarily due to a remarkable 90% reduction in food intake within the first day (Loftus et al., 2000). The feeding behavior as well as the body weight returned to normal as the drug effect wore off, indicating that the observed effect was not due to a toxicity-induced state of permanent wasting (Loftus et al., 2000). As far as the neuropeptide control of feeding is concerned, hypothalamic NPY mRNA levels in C75-treated mice were lower than in fed control mice, indicating that the C75-induced mechanism of anorexia may work via the inhibition of NPY-induced feeding (Loftus et al., 2000). This mechanism likely lies upstream of NPY activation, as i.c.v. NPY treatment in C75 pretreated mice led to pronounced feeding behavior (Loftus et al., 2000). Leptin had long been championed as a primary anorexigenic factor, however, the ability of C75 treatment to work in leptin-deficient “ob/ob” mice (Loftus et al., 2000) illustrates that the anorexigenic behavior initiated by FAS-inhibition is actually independent of leptin action. The potential of a central impact of C75 was demonstrated in two ways: (1) studies with a radiolabeled variant of the drug illustrated that C75 indeed enters the brain and (2) direct, i.c.v. administration of C75, much like i.c.v. cerulenin, inhibited feeding by greater than 80%. Overall, the data is supportive of the aforementioned hypothesis, according to which malonyl-CoA signals a fuel status to trigger satiety signals in the hypothalamus.

In the attempt to link the role of malonyl-CoA with FAS in the regulation of feeding behavior, it was demonstrated in a subsequent study that i.c.v. administration of C75 in fasted animals increased hypothalamic malonyl-CoA concentrations by fourfold (Hu et al., 2003). By administering an ACC inhibitor centrally to prevent the rise in malonyl-CoA accumulation, it was found that the C75-induced anorexia and neuropeptide mRNA changes were abolished (Hu et al., 2003).

It is clear from such findings that hypothalamic regulation of energy homeostasis is a complex series of processes involving many metabolites and enzymes. Particularly, the anorexic effects triggered by ACC activation combined with the opposing orexigenic effects of AMPK activation would strongly imply that malonyl-CoA, a downstream product of ACC, must hold a critical role in such sensing pathway. Indeed, the concentration of malonyl-CoA in the hypothalamus falls during fasting and rises after refeeding (Hu et al., 2003). Further, malonyl-CoA is also involved in nutrient and hormonal sensing in the hypothalamus. Specifically, central glucose and leptin have recently been confirmed to regulate hypothalamic malonyl-CoA concentrations (Wolfgang et al., 2007). It was found that malonyl-CoA level in the hypothalamus rises upon peripheral glucose administration, but is blocked when central glucose metabolism is pharmacologically inhibited. Further, a single dose of i.c.v. leptin induces a sustained increase in hypothalamic malonyl-CoA level, which flawlessly compliments previous findings that central glucose and leptin lowered hypothalamic AMPK activity (Andersson et al., 2004; Minokoshi et al., 2004) while the latter was also found to augment hypothalamic ACC activity (Gao et al., 2007). These kinetic changes in AMPK, ACC, FAS, and malonyl-CoA are perhaps not merely coincidental and strongly support the existence of an underlying link between these individual factors.

The above finding suggests a potential integration and codependence between the fatty acid biosynthesis and glucose metabolism pathways in the hypothalamus when it comes to the regulation of energy balance. Noting that neuronal metabolism is essentially solely dependent on glucose supply for energy, Wortman and colleagues tested the idea that the anorexic effects of C75 administration requires increased glucose utilization as opposed to decreased lipid utilization (Wortman et al., 2003). In this study, rats maintained on a very low-carbohydrate diet to induce ketosis did not exhibit the decreased short-term food intake or body weight in response to i.c.v. C75; interestingly, i.c.v. C75’s anorectic ability was restored when ketogenic animals were provided with a 10% sucrose drink (Wortman et al., 2003). To further assess the need for increased central glucose utilization due to C75’s anorectic effects, the authors coadministered glutamine or lactate—energy sources provided to neurons by glial metabolism—with i.c.v. C75. In the presence of glutamate or lactate, there is a reduced need for neurons to metabolize glucose, so according to the proposed theory, C75’s effect should be negated in this environment; indeed, they found that administering glutamate or lactate was sufficient to negate the anorexia induced by i.c.v. C75 (Wortman et al., 2003). Thus, it is quite likely that the regulation of energy balance mediated by inhibition of FAS is reliant on central glucose use.

The studies thus far have focused on FAS inhibition and its role in the suppression of food intake, however, it has also been shown that C75-induced weight loss is also due to an increase in energy expenditure (Kumar et al., 2002). A follow-up study by M.D. Lane’s group investigated the possibility that an increased rate of fatty acid oxidation accounted for this observed increase in energy expenditure. The central administration (i.c.v.) of C75 to fasted mice caused a significant increase in (1) whole-body fatty acid oxidation, as determined in vivo and (2) skeletal muscle fatty acid oxidation, as determined in vitro; in response to this, there was also a concomitant increase in the expression of PPARα, which activates the expression of genes encoding enzymes of fatty acid oxidation (Cha et al., 2005). Interestingly, when phentolamine, an agent that blocks α-adrenergic (sympathetic nervous system) transmission, was used, the effects of i.c.v. C75 on whole body and skeletal muscle fatty acid oxidation were negated (Cha et al., 2005). Thus, the results indicate that the hypothalamic signal mediated by FAS-inhibition to increase energy expenditure occurs via nervous transmission to the skeletal muscle to increase fatty acid oxidation.

Though the evidence for the role of FAS in hypothalamic energy regulation thus far appears indisputable, a few legitimate concerns persist. First, while the pharmacological inhibition of FAS with C75 provided the basis of much of the evidence on FAS, it is made clear in recent years that C75 is, in fact, nonspecific, having complex effects including activation of the sympathetic nervous system (Cha et al., 2005; Chakravarthy et al., 2007), as mentioned previously. Further, while i.c.v. inhibition of FAS is known to increase the expression of PPARα in the periphery, the effects of central PPARα remain unknown. To tackle these questions, brain-beta cell-specific FAS knockout mice were generated (Charkravarthy et al., 2007).

Using a rat insulin promoter, FAS was elegantly and specifically knocked out in the beta cells and brain. It was first established in the study that FAS knockout had no effect on beta cell function or visible changes in islet morphology, indicating that FAS was not required for beta-cell function in adult mice (Charkravarthy et al., 2007). With that established, it was reasonable to attribute the observed changes to the absence of central FAS. In line with the findings previously described, central FAS knockout had disrupted energy balance, with altered feeding behaviors and energy expenditure. These mice exhibited a lean, hypophagic phenotype with increased physical activity compared to control animals (Charkravarthy et al., 2007). In situ hybridization revealed a suppression of mRNAs for orexigenic neuropeptides, i.e., NPY and AgRP, and induction of anorexigenic neuropeptides, i.e., POMC and cocaine-amphetamine-related transcript (CART) in the ARC of the hypothalamus (Charkravarthy et al., 2007). Furthermore, it was seen that central FAS, besides activating peripheral PPARα (Cha et al., 2005), also activates brain PPARα to coordinate feeding behaviors (Charkravarthy et al., 2007). The authors reported a 50% reduction of mRNA levels of acyl-CoA oxidase (ACO), CPT1, and MCD, all of which are known targets of PPARα (Charkravarthy et al., 2007). However, in order to confirm that PPARα is indeed a critical downstream effector of FAS’ energy regulation, the authors administered a potent PPARα agonist Wy14643 centrally in an attempt to rescue the FAS knockout phenotype. Strikingly, such agonist administration was able to rescue the food intake and body weight decrease in the knockout animals under fasted conditions and restored the mRNA levels of PPARα target genes, i.e., ACO, CPT1, and MCD. Further, Wy14643 injected in the ventral hypothalamus in these knockout animals actually resulted in increased food intake under ad libitum settings compared to wild-type controls (Charkravarthy et al., 2007).


The recent past has yielded novel and exciting experimental data that have furthered the concept that the hypothalamus is a key regulator of energy balance and glucose homeostasis, revealing new metabolic and hormonal signaling factors along the way. However, a necessary step is to flesh out these findings in models of metabolic disease (obesity, insulin resistance and/or diabetes) in order to gain an appreciation of what went wrong—and possibly what is still going strong—when it comes to the centrally-mediated homeostatic mechanisms in pathology.

As mentioned earlier, an increase in central fatty acid levels is able to trigger a hypothalamic mechanism to curb food intake and GP (Obici et al., 2002a,b), the latter of which is KATP channel-dependent; circulating fatty acids also were demonstrated to initiate a similar regulatory response in the suppression of GP (Lam et al., 2005a–c). Remarkably, providing rats with a high-fat diet for a mere 3 days was sufficient to nullify these homeostatic effects (Lam et al., 2005a–c; Morgan et al., 2004). It appears as if overfeeding elevated the basal activity of the enzyme CPT1, resulting in an absence of the LCFA-CoA signal, as the inhibition of this enzyme with multiple approaches was able to restore the ability of hypothalamic lipids to suppress food intake and GP (Pocai et al., 2006). These methodical studies by the Rossetti group clearly demonstrated the role of fatty acid oxidation shunting in the hypothalamus in generating the local LCFA-CoA trigger to serve as a behavioral and metabolic surfeit signal.

Long known to serve as a cellular energy sensor, even in the most simplest of organisms, AMPK has recently been shown to have a regulatory role in the hypothalamus-mediated control of energy balance (Minokoshi et al., 2004). With the fatty acid biosynthetic pathway in mind, the accumulation of intracellular malonyl-CoA and LCFA-CoA would be antagonized by AMPK hyperactivity, and a number of studies have examined this potential dysregulation of AMPK activity in obese or diabetic models. Streptozotocin (STZ)-induced diabetic rats are eventually characterized by marked hyperphagia, and compared with control rodents, it was found that hypothalamic AMPK activity was higher in diabetic rats; this activity (and the resultant food intake) was normalized by the i.c.v. administration of an AMPK inhibitor, as well as insulin and leptin (Namkoong et al., 2005), confirming the previously established central anorectic effects of those hormones. Additionally, in a 12-week model of diet-induced obesity, leptin’s ability to inhibit AMPK activity in various hypothalamic nuclei, including the ARC, was lost (Martin et al., 2006). Conversely, it was recently found out that mice that were absent in CaMKK2, a regulator of AMPK activity, were protected from diet-induced obesity, insulin resistance, and glucose intolerance (Anderson et al., 2008).

Obesity and diabetes are typically characterized by hyperphagia, hyperinsulinemia, and hyperleptinemia, and as a result, profound insulin and leptin resistance can occur. Studies have shown that central pathways play a part in bestowing these resistant phenotypes. In a landmark study nearly 30 years ago, Woods and colleagues demonstrated that the chronic central infusion of insulin reduces food intake and body weight (Woods et al., 1979); however, in animals receiving a high-fat diet for 14 days, a chronic, one-week infusion of central insulin failed to reproduce these anorectic effects (Arase et al., 1988). Furthermore, the i.c.v. infusion of a phosphatidylinositol 3-kinase (PI3K) inhibitor blunted the ability of peripheral insulin injection to normalize glucose levels in STZ-diabetic rodents, convincingly demonstrating the importance of central insulin signaling in the brain during insulin treatment (Gelling et al., 2006). The adipokine leptin, once hailed as the next possible “miracle cure,” faces a particularly interesting problem as far as the brain is concerned. Peripherally administered leptin normally acts through a hypothalamic STAT3-signaling pathway to exert its anorectic effects, however, a prolonged high-fat diet was found to eradicate this ability in rodents (El-Haschimi et al., 2000). Interestingly, these diet-induced obese rodents were still responsive to the effects of centrally administered insulin (El-Haschimi et al., 2000). Thus in the obese state, it is not necessarily the action of leptin that is compromised; rather, there is likely defective leptin transport from circulation into the CNS.

A noteworthy study recently implicated apolipoprotein E (ApoE) as yet another mediator of the central control of energy homeostasis. Predominantly produced in the brain and the liver, and shown in the brain to have effects on oxidative stress protection and regulating local immune responses, i.c.v. ApoE was demonstrated to have markedly decreased food intake via a POMC-stimulating mechanism in lean mice (Shen et al., 2008). Dysregulation of central ApoE may be a critical event in hyperphagia and resultant obesity, as in both diet-induced obese and leptin-deficient “ob/ob” rodents had significantly reduced hypothalamic “apoE” mRNA levels (Shen et al., 2008).

While each of these observed defects hint at varying alterations in metabolic signals and/or enzymatic activities per se as a potential root cause in the defects mediating the loss in hypothalamic signal effectiveness to regulate homeostasis, a very recent publication hints that there may indeed be a common defect underlying them all. Bouret and colleagues observed that rats that were selectively bred to develop diet-induced obesity develop defective ARC neuronal projections (Bouret et al., 2008). Leptin, which is essential for the normal development of ARC projections, was found to be ineffective in activating ARC neuron signaling in diet-induced obese neonates (Bouret et al., 2008). Thus, it is quite likely that the genetically governed structural defects persist into adulthood and play a key role in initiation and progression of ineffective hypothalamic surfeit signaling.

But interestingly, not all central sensing mechanisms are disrupted in models of obesity and/or diabetes. For example, an acute increase in central or hypothalamic lactate has been shown to regulate glucose homeostasis by suppressing GP in normal rodents (Lam et al., 2005a–c). Interestingly, we have also observed that administration of central lactate—at the same dose used in normal rodents is able to lower GP in an early-onset model of STZ-Diabetes (Chari et al., 2008). Furthermore, central lactate suppressed GP in normal rodents with experimentally induced hypoinsulinemia, and more significantly, in diet-induced insulin resistance resulting from a 3 day high-fat diet (Chari et al., 2008). It is intriguing that in a similar model of acute diet-induced insulin resistance, central oleic acid was ineffective in suppressing food intake and GP (Morgan et al., 2004). Clearly, further investigation is necessary to elucidate the mechanism underlying this selective loss in central nutrient sensing.


Although the glucostatic and lipostatic theories were presented well over half a century ago, the nature of the input signal required for the hypothalamic regulation of nutrient and energy homeostasis and the related biochemical mechanism had remained unclear until the recent past. Numerous landmark studies have made significant contributions to the advancement of the field, and have collectively proven that certain hypothalamic nuclei respond to shifts in energy and nutrient status relayed by circulating factors, including metabolites as well as hormones, to initiate behavioral and metabolic changes to restore energy and glucose homeostasis (Sandoval et al., 2008). Thus, there is an undeniable importance of the CNS in the development of what seems like primarily peripheral metabolic diseases of obesity and diabetes.

In specific, this review highlights the importance of generating the LCFA-CoA surfeit signal as a result of hypothalamic fatty acid biosynthesis and utilization in mediating these homeostatic responses. Keen observers will be quick to notice that this idea is at complete odds with the effect of circulating LCFAs—namely, the induction of insulin resistance and an increase in GP (Lam et al., 2003). This might seem paradoxical; however, we propose that these two seemingly contradictory processes, as far as diabetogenic processes and metabolic dysfunction is concerned, can work harmoniously in the monitoring of energy and nutrient status. In fact, we propose that a balance in central and hepatic lipid sensing exists (Caspi et al., 2007), whereby the opposing effects of lipid sensing in these two organs achieve an equilibrium in GP regulation. In the event that this balance is disrupted, such as in the obese state, a dysregulation in GP will result, facilitating the progression of diabetes.

But the picture is far from complete. While the transmission from the first-order neurons in the ARC to second-order neurons in other hypothalamic nuclei is generally accepted, it can still be argued in the present that the efferent mechanism by which hypothalamic signaling is linked to metabolism in peripheral tissues remains largely unknown (Horvath et al., 2004; Schwartz and Porte, 2005). One possible mechanism may use vagal outflow to the liver, as hepatic vagotomy has been shown to nullify the ability of central inhibition of fat oxidation to suppress GP (Pocai et al., 2005). And while the bulk of the research has focused on the ARC, other brain nuclei (hypothalamic or otherwise) could likely be involved in the processing of peripheral hormone and nutrient signals (Schwartz and Porte, 2005).

Thus, continued efforts are necessary in order to fully characterize the nutrient, nervous, or hormone-mediated responses in the brain and the extent to which they may be altered in the diseased metabolic state. This will undoubtedly lead to a prioritization of possible central targets when it comes to developing novel therapeutics to combat the rapidly increasing obesity and diabetes epidemic.


  1. Abu-Elheiga L, Matzuk MM, Abo-Hashema KAH, Wakil SJ. Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-coA carboxylase 2. Science. 2001;291:2613–2616. [PubMed: 11283375]
  2. Abu-Elheiga L, Matzuk MM, Kordari P, Oh W, Shaikenov T, Gu Z, Wakil SJ. Mutant mice lacking acetyl-coA carboxylase 1 are embryonically lethal. Proc Natl Acad Sci. 2005;102:12011–12016. [PMC free article: PMC1189351] [PubMed: 16103361]
  3. Adage T, Scheurink AJ, de Boer SF, de Vries K, Konsman JP, Kuipers F, Adan RA, Baskin DG, Schwartz MW, van Dijk G. Hypothalamic, metabolic, and behavioral responses to pharmacological inhibition of CNS melanocortin signalling in rats. J Neurosci. 2001;21:3639–3645. [PubMed: 11331393]
  4. Andersson U, Filipsson K, Abbott CR, Woods A, Smith K, Bloom SR, Carling D, Small CJ. AMP-activated protein kinase plays a role in the control of food intake. J Biol Chem. 2004;279:12005–12008. [PubMed: 14742438]
  5. Anderson KA, Ribar TJ, Lin F, Noeldner PK, Green MF, Muehlbauer MJ, Witters LA, Kemp BE, Means AR. Hypothalamic CaMKK2 contributes to the regulation of energy balance. Cell Metab. 2008;7:377–388. [PubMed: 18460329]
  6. Arase K, Fisler JS, Shargill NS, York DA, Bray GA. Intracerebroventricular infusions of 3-OHB and insulin in a rat model of dietary obesity. Am J Physiol. 1988;255:R974–R981. [PubMed: 3059829]
  7. Benoit SC, Air EL, Coolen LM, Strauss R, Jackman A, Clegg DJ, Seeley RJ, Woods SC. The catabolic action of insulin in the brain is mediated by melanocortins. J Neurosci. 2002;22:9048–9052. [PubMed: 12388611]
  8. Bence KK, Delibegovic M, Xue B, Gorgun CZ, Hotamisligil GS, Neel BG, Kahn BB. Neuronal PTP1B regulates body weight, adiposity and leptin action. Nat Med. 2006;12:917–924. [PubMed: 16845389]
  9. Bouret SG, Gorski JN, Patterson CM, Chen S, Levin BE, Simerly RB. Hypothalamic neural projections are permanently disrupted in diet-induced obese rats. Cell Metab. 2008;7:179–185. [PMC free article: PMC2442478] [PubMed: 18249177]
  10. Calle EE, Kaaks R. Overweight, obesity and cancer: Epidemiological evidence and proposed mechanisms. Nat Rev Cancer. 2004;4:579–591. [PubMed: 15286738]
  11. Caspi L, Wang PY, Lam TK. A balance of lipid-sensing mechanisms in the brain and liver. Cell Metab. 2007;6:99–104. [PubMed: 17681145]
  12. Cesquini M, Stoppa GR, Prada PO, Torsoni AS, Romanatto T, Souza A, Saad MJ, Velloso LA, Torsoni MA. Citrate diminishes hypothalamic acetyl-coA carboxylase phosphorylation and modulates satiety signals and hepatic mechanisms involved in glucose homeostasis in rats. Life Sci. 2008;82:1262–1271. [PubMed: 18534630]
  13. Cha SH, Hu Z, Chohnan S, Lane MD. Inhibition of hypothalamic fatty acid synthase triggers rapid activation of fatty acid oxidation in skeletal muscle. Proc Natl Acad Sci. 2005;102:14557–14562. [PMC free article: PMC1253598] [PubMed: 16203972]
  14. Chakravarthy MV, Zhu Y, Lopez M, Yin L, Wozniak DF, Coleman T, Hu Z, et al. Brain fatty acid synthase activates PPARα to maintain energy homeostasis. J Clin Invest. 2007;117:2539–2552. [PMC free article: PMC1937501] [PubMed: 17694178]
  15. Chari M, Lam CK, Wang PY, Lam TK. Activation of central lactate metabolism lowers glucose production in uncontrolled diabetes and diet-induced insulin resistance. Diabetes. 2008;57:836–840. [PubMed: 18184925]
  16. Choi CS, Savage DB, Abu-Elheiga L, Liu ZX, Kim S, Kulkarni A, Distefano A, et al. Continuous fat oxidation in acetyl-coA carboxylase 2 knockout mice increases total energy expenditure, reduces fat mass, and improves insulin sensitivity. Proc Natl Acad Sci. 2007;104:16480–16485. [PMC free article: PMC2034222] [PubMed: 17923673]
  17. Clark JT, Kalra PS, Kalra SP. Neuropeptide Y stimulates feeding but inhibits sexual behavior in rats. Endocrinology. 1985;117:2435–2442. [PubMed: 3840737]
  18. Claret M, Smith MA, Batterham RL, Selman C, Choudhury AI, Fryer LGD, Clements M, et al. AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons. J Clin Invest. 2007;117:2325–2336. [PMC free article: PMC1934578] [PubMed: 17671657]
  19. Cone RD. Anatomy and regulation of the central melanocortin system. Nat Neurosci. 2005;8:571–578. [PubMed: 15856065]
  20. Coppari R, Ichinose M, Lee CE, Pullen AE, Kenny CD, McGovern RA, Tang V, et al. The hypothalamic arcuate nucleus: A key site for mediating leptin’s effects on glucose homeostasis and locomotor activity. Cell Metab. 2005;1:63–72. [PubMed: 16054045]
  21. Cota D, Proulx K, Smith KA, Kozma SC, Thomas G, Woods SC, Seeley RJ. Hypothalamic mTOR signaling regulates food intake. Science. 2006;312:927–930. [PubMed: 16690869]
  22. Cowley MA, Smart JL, Rubinstein M, Cerdán MG, Diano S, Horvath TL, Cone RD, Low MJ. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature. 2001;411:480–484. [PubMed: 11373681]
  23. El-Haschimi K, Pierroz DD, Hileman SM, Bjørbaek C, Flier JS. Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity. J Clin Invest. 2000;105:1827–1832. [PMC free article: PMC378516] [PubMed: 10862798]
  24. Flier JS. Obesity wars: Molecular progress confronts and expanding epidemic. Cell. 2004;116:337–350. [PubMed: 14744442]
  25. Friedman MI. An energy sensor for control of food intake. Proc Nutr Soc. 1997;56:41–50. [PubMed: 9168519]
  26. Friedman JM. A war on obesity, not the obese. Science. 2003;299:856–858. [PubMed: 12574619]
  27. Gao S, Lane MD. Effect of the anorectic fatty acid synthase inhibitor C75 on neuronal activity in the hypothalamus and brainstem. Proc Natl Acad Sci. 2003;100:5628–5633. [PMC free article: PMC156252] [PubMed: 12724522]
  28. Gao S, Kinzig KP, Aja S, Scott KA, Keung W, Kelly S, Strynadka K, et al. Leptin activates hypothalamic acetyl-coA carboxylase to inhibit food intake. Proc Natl Acad Sci. 2007;104:17358–17363. [PMC free article: PMC2077261] [PubMed: 17956983]
  29. Gelling RW, Morton GJ, Morrison CD, Niswender KD, Myers MG Jr, Rhodes CJ, Schwartz MW. Insulin action in the brain contributes to glucose lowering during insulin treatment of diabetes. Cell Metab. 2006;3:67–73. [PubMed: 16399506]
  30. Goto M, Arima H, Watanabe M, Hayashi M, Banno R, Sato I, Nagasaki H, Oiso Y. Ghrelin increases neuropeptide Y and agouti-related peptide gene expression in the arcuate nucleus in rat hypothalamic organotypic cultures. Endocrinology. 2006;147:5102–5109. [PubMed: 16887908]
  31. Hardie DG, Carling D. The AMP-activated protein kinase: Fuel gauge of the mammalian cell? Eur J Biochem. 1997;246:259–273. [PubMed: 9208914]
  32. Hetherington A, Ranson S. The spontaneous activity and food intake of rats with hypothalamic lesions. Am J Physiol. 1942;136:609–617.
  33. Hawley SA, Boudeau J, Reid JK, Mustard KJ, Udd L, Makela TP, Alessi DR, Hardie DG. Complexes between the LKB2 tumor suppressor, STRADα/β and MO25α/β are upstream kinases in the AMP-activated protein kinase cascade. J Biol. 2003;2:28. [PMC free article: PMC333410] [PubMed: 14511394]
  34. Hawley SA, Pan DA, Mustard KJ, Ross L, Bain J, Edelman AM, Frenguelli BG, Hardie DG. Calmodulin-dependent protein kinase kinase-β is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab. 2005;2:9–19. [PubMed: 16054095]
  35. He W, Lam TK, Obici S, Rossetti L. Molecular disruption of hypothalamic nutrients sensing induces obesity. Nat Neurosci. 2006;9:227–233. [PubMed: 16415870]
  36. Horvath TL, Diano S, Tschöp M. Brain circuits regulating energy homeostasis. Neuroscientist. 2004;10:235–246. [PubMed: 15155062]
  37. Hossain P, Kawar B, El Nahas M. Obesity and diabetes in the developing world—A growing challenge. N Engl J Med. 2007;356:213–215. [PubMed: 17229948]
  38. Hu Z, Cha SH, Chohnan S, Lane MD. Hypothalamic malonyl-CoA as a mediator of feeding behaviour. Proc Natl Acad Sci. 2003;100:12624–12629. [PMC free article: PMC240668] [PubMed: 14532332]
  39. Hu Z, Dai Y, Prentki M, Chohnan S, Lane MD. A role for hypothalamic malonyl-CoA in the control of food intake. J Biol Chem. 2005;280:39681–39683. [PubMed: 16219771]
  40. Hurley RL, Anderson KA, Franzone JM, Kemp BE, Means AR, Witters LA. The Ca2+/calmodulin-dependent protein kinase kinases are AMP-activated protein kinase kinases. J Biol Chem. 2005;280:29060–29066. [PubMed: 15980064]
  41. Inoue H, Ogawa W, Asakawa A, Okamoto Y, Nishizawa A, Matsumoto M, Teshigawara K, et al. Role of hepatic STAT3 in brain-insulin action on hepatic glucose production. Cell Metab. 2006;3:267–275. [PubMed: 16581004]
  42. Kahn BB, Alquier T, Carling D, Hardie DG. AMP-activated protein kinase: Ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab. 2005;1:15–25. [PubMed: 16054041]
  43. Kamohara S, Burcelin R, Halaas JL, Friedman JM, Charron MJ. Acute stimulation of glucose metabolism in mice by leptin treatment. Nature. 1997;389:374–377. [PubMed: 9311777]
  44. Kennedy GC. The role of depot fat in the hypothalamic control of food intake in the rat. Proc Royal Soc (Lond). 1953;140B:578–596. [PubMed: 13027283]
  45. Kievit P, Howard JK, Badman MK, Balthasar N, Coppari R, Mori H, Lee CE, Elmquist JK, Yoshimura A, Flier JS. Enhanced leptin sensitivity and improved glucose homeostasis in mice lacking suppressor of cytokine signaling-3 in POMC-expressing cells. Cell Metab. 2006;4:123–132. [PubMed: 16890540]
  46. Kim EK, Miller I, Landree LE, Borisy-Rudin FF, Brown P, Tihan T, et al. Expression of FAS within hypothalamic neurons: a model for decreased food intake after C75 treatment. Am J Physiol Endocrinol Metab. 2002;283:E867–E879. [PubMed: 12376313]
  47. Kim EK, Miller I, Aja S, Landree LE, Pinn M, McFadden J, Kuhajda FP, Moran TH, Ronnett GV. C75, a fatty acid synthase inhibitor, reduces food intake via hypothalamic AMP-activated protein kinase. J Biol Chem. 2004;279:19970–19976. [PubMed: 15028725]
  48. Kim MS, Park JY, Namkoong C, Jang RG, Ryu JW, Song HS, Yun JY, et al. Anti-obesity effects of alpha-lipoic acid mediated by suppression of hypothalamic AMP-activated protein kinase. Nat Med. 2004;10:727–733. [PubMed: 15195087]
  49. Kola B, Hubina E, Tucci SA, Kirkham TC, Garcia EA, Mitchell SE, Williams LM, et al. Cannabinoids and ghrelin have both central and peripheral metabolic and cardiac effects via AMP-activated protein kinase. J Biol Chem. 2005;280:25196–25201. [PubMed: 15899896]
  50. Könner AC, Janoschek R, Plum L, Jordan SD, Rother E, Ma X, Xu C, et al. Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. Cell Metab. 2007;5:438–449. [PubMed: 17550779]
  51. Kubota N, Yano W, Kubota T, Yamauchi T, Itoh S, Kumagai H, Kozono H, et al. Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake. Cell Metab. 2007;6:55–68. [PubMed: 17618856]
  52. Kumar MV, Shimokawa T, Nagy TR, Lane MD. Differential effects of a centrally acting fatty acid synthase inhibitor in lean and obese mice. Proc Natl Acad Sci. 2002;99:1921–1925. [PMC free article: PMC122295] [PubMed: 11854492]
  53. Lam TK, Carpentier A, Lewis GF, van de Werve G, Fantus IG, Giacca A. Mechanisms of the free fatty acid-induced increase in hepatic glucose production. Am J Physiol Endocrinol Metab. 2003;284:E863–873. [PubMed: 12676648]
  54. Lam TK, Gutierrez-Juarez R, Pocai A, Rossetti L. Regulation of blood glucose by hypothalamic pyruvate metabolism. Science. 2005a;309:943–947. [PubMed: 16081739]
  55. Lam TK, Pocai A, Gutierrez-Juarez R, Obici S, Bryan J, Aguilar-Bryan L, Schwartz GJ, Rossetti L. Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis. Nat Med. 2005b;11:320–327. [PubMed: 15735652]
  56. Lam TK, Schwartz GJ, Rossetti L. Hypothalamic sensing of fatty acids. Nat Neurosci. 2005c;8:579–584. [PubMed: 15856066]
  57. Lam CK, Chari M, Wang PY, Lam TK. Central lactate metabolism regulates food Intake. Am J Physiol Endocrinol Metab. 2008;295:E491–E496. [PubMed: 18577696]
  58. Langhans W. Metabolic and glucostatic control of feeding. Proc Nutr Soc. 1996;55:497–515. [PubMed: 8832815]
  59. Lee K, Li B, Xi X, Suh Y, Martin RJ. Role of neuronal energy status in the regulation of adenosine 5′-monophosphate-activated protein kinase, orexigenic neuropeptides expression, and feeding behavior. Endocrinology. 2005;146:3–10. [PubMed: 15375032]
  60. Lelliott C, Vidal-Puig AJ. Lipotoxicity, an imbalance between lipogenesis de novo and fatty acid oxidation. Int J Obes Relat Metab Disord. 2004;28:S22–S28. [PubMed: 15592482]
  61. Loftus TM, Jaworsky DE, Frehywot GL, Townsend CA, Ronnett GV, Lane MD, Kuhajda FP. Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science. 2000;288:2379–2381. [PubMed: 10875926]
  62. López M, Vidal-Puig A. Brain lipogenesis and regulation of energy metabolism. Curr Opin Clin Nutr Metab Care. 2008;11:483–490. [PubMed: 18542011]
  63. López M, Lelliot CJ, Vidal-Puig AJ. Hypothalamic fatty acid metabolism: A housekeeping pathway that regulates food intake. BioEssays. 2007;29:248–261. [PubMed: 17295284]
  64. Luheshi GN, Gardner JD, Rushforth DA, Loudon AS, Rothwell NJ. Leptin actions on food intake and body temperature are mediated by IL-1. Proc Nat Acad Sci. 1999;96:7047–7052. [PMC free article: PMC22051] [PubMed: 10359836]
  65. Martin TL, Alquier T, Asakura K, Furukawa N, Preitner F, Kahn BB. Diet-induced obesity alters AMP kinase activity in hypothalamus and skeletal muscle. J Biol Chem. 2006;281:18933–189341. [PubMed: 16687413]
  66. Mayer J. Glucostatic mechanism of regulation of food intake. N Engl J Med. 1953;249:13–16. [PubMed: 13063674]
  67. McGarry JD, Leatherman GF, Foster DW. Carnitine palmitoyltransferase I: The site of inhibition of hepatic fatty acid oxidation by malonyl-coA. J Biol Chem. 1978;253:4128–4136. [PubMed: 659409]
  68. Miller JC, Gnaedinger JM, Rapoport SI. Utilization of plasma fatty acid in rat brain: distribution of [14C] palmitate between oxidative and synthetic pathways. J Neurochem. 1987;49:1507–1514. [PubMed: 2889801]
  69. Minokoshi Y, Kim YB, Peroni OD, Fryer LGD, Muller C, Carling D, Kahn BB. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature. 2002;415:339–343. [PubMed: 11797013]
  70. Minokoshi Y, Alquier T, Furukawa N, Kim YB, Lee A, Xue B, Mu J, et al. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature. 2004;428:569–574. [PubMed: 15058305]
  71. Miselis RR, Epstein AN. Feeding induced by intracerebroventricular 2-deoxy-D-glucose in the rat. Am J Physiol. 1975;229:1438–1437. [PubMed: 1200165]
  72. Morgan K, Obici S, Rossetti L. Hypothalamic responses to long-chain fatty acids are nutritionally regulated. J Biol Chem. 2004;279:31139–31148. [PubMed: 15155754]
  73. Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW. Central nervous system control of food intake and body weight. Nature. 2006;443:289–295. [PubMed: 16988703]
  74. Munday MR, Carling D, Hardie DG. Negative interactions between phosphorylation of acetyl-CoA carboxylase by the cyclic AMP-dependent and AMP-activated protein kinases. FEBS Letters. 1988;235:144–148. [PubMed: 2900158]
  75. Namkoong C, Kim MS, Jang PG, Han SM, Park HS, Koh EH, Lee WJ, Kim JY, Park IS, Park JY, Lee KU. Enhanced hypothalamic AMP-activated protein kinase activity contributes to hyperphagia in diabetic rats. Diabetes. 2005;54:63–68. [PubMed: 15616011]
  76. Obici S, Feng Z, Morgan K, Stein D, Karkanias G, Rossetti L. Central administration of oleic acid inhibits glucose production and food intake. Diabetes. 2002a;51:271–275. [PubMed: 11812732]
  77. Obici S, Zhang BB, Karkanias G, Rossetti L. Hypothalamic insulin signalling is required for inhibition of glucose production. Nat Med. 2002b;8:1376–1382. [PubMed: 12426561]
  78. Obici S, Feng Z, Arduini A, Conti R, Rossetti L. Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production. Nat Med. 2003;9:756–761. [PubMed: 12754501]
  79. Ollmann MM, Wilson BD, Yang YK, Kerns JA, Chen Y, Gantz I, Barsh GS. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science. 1997;278:135–138. [PubMed: 9311920]
  80. Plum L, Ma X, Hampel B, Balthasar N, Coppari R, Münzberg H, Shanabrough M, et al. Enhanced PIP3 signalling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity. J Clin Invest. 2006;116:1886–1901. [PMC free article: PMC1481658] [PubMed: 16794735]
  81. Pocai A, Lam TK, Gutierrez-Juarez R, Obici S, Schwartz GJ, Bryan J, Aguilar-Bryan L, Rossetti L. Hypothalamic K(ATP) channels control hepatic glucose production. Nature. 2005;434:1026–1031. [PubMed: 15846348]
  82. Pocai A, Obici S, Schwartz GJ, Rossetti L. A brain-liver circuit regulates glucose homeostasis. Cell Metab. 2005;1:53–61. [PubMed: 16054044]
  83. Pocai A, Lam TK, Obici S, Gutierrez-Juarez R, Muse ED, Arduini A, Rossetti L. Restoration of hypothalamic lipid sensing normalizes energy and glucose homeostasis in overfed rats. J Clin Invest. 2006;116:1081–1091. [PMC free article: PMC1395479] [PubMed: 16528412]
  84. Price N, van der Leij F, Jackson V, Corstorphine C, Thomson R, Sorensen A, Zammit V. A novel brain-expressed protein related to carnitine palmitoyltransferase I. Genomics. 2002;80:433–442. [PubMed: 12376098]
  85. Ramamurthy S, Ronnett GV. Developing a head for energy sensing: AMP-activated protein kinase as a multifunctional metabolic sensor in the brain. J Physiol. 2006;574:85–93. [PMC free article: PMC1817796] [PubMed: 16690704]
  86. Roman EA, Cesquini M, Stoppa GR, Carvalheira JB, Torsoni MA, Velloso LA. Activation of AMPK in rat hypothalamus participates in cold-induced resistance to nutrient-dependent anorexigenic signals. J Physiol. 2005;568:993–1001. [PMC free article: PMC1464170] [PubMed: 16141267]
  87. Rowan A, Churchman M, Jefferey R, Hanby A, Poulsom R, Tomlinson I. In situ analysis of LKB1/STK11 mRNA expression in human normal tissues and tumours. J Pathol. 2000;92:203–206. [PubMed: 11004696]
  88. Sandoval D, Cota D, Seeley RJ. The integrative role of CNS fuel-sensing mechanisms in energy balance and glucose regulation. Annu Rev Physiol. 2008;70:513–535. [PubMed: 17988209]
  89. Sato I, Arima H, Ozaki N, Watanabe M, Goto M, Hayashi M, Banno R, Nagasaki H, Oiso Y. Insulin inhibits neuropeptide Y gene expression in the arcuate nucleus through GBAergic systems. J Neurosci. 2005;25:8657–8664. [PubMed: 16177033]
  90. Schwartz MW, Porte D Jr. Diabetes, obesity and the brain. Science. 2005;307:375–379. [PubMed: 15662002]
  91. Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG. Central nervous system control of food intake. Nature. 2000;404:661–671. [PubMed: 10766253]
  92. Seeley RJ, Woods SC. Monitoring of stored and available fuel by the CNS: Implications for Obesity. Nat Rev Neurosci. 2003;4:901–909. [PubMed: 14595401]
  93. Seifter S, Englard S. Energy metabolism. In: Arias IM, Jakoby WB, Popper H, Schachter D, Shafritz DA, editors. The Liver: Biology and Pathobiology. New York: Raven Press; 1988. pp. 279–315.
  94. Seo S, Ju S, Chung H, Lee D, Park S. Acute effects of glucagon-like peptide-1 on hypothalamic neuropeptide and AMP activated kinase expression in fasted rats. Endocr J. 2008;55:867–874. [PubMed: 18506089]
  95. Shen L, Tso P, Woods SC, Clegg DJ, Barber KL, Carey K, Liu M. Brain apolipoprotein E: An important regulator of food intake in rats. Diabetes. 2008;57:2092–2098. [PMC free article: PMC2494691] [PubMed: 18559657]
  96. Shimizu H, Arima H, Watanabe M, Goto M, Banno R, Sato I, Ozaki N, Nagasaki H, Oiso Y. Glucocorticoids increase neuropeptide Y and agouti-related peptide gene expression via AMP-activated protein kinase signaling in the arcuate nucleus of rats. Endocrinology. 2008;149:4544–4453. [PubMed: 18535107]
  97. Sim AT, Hardie DG. The low activity of acetyl-CoA carboxylase in basal and glucagon-stimulated hepatocytes is due to phosphorylation by the AMP-activated protein kinase and not cyclic AMP-dependent protein kinase. FEBS Lett. 1988;233:294–298. [PubMed: 2898386]
  98. Spanswick D, Smith MA, Groppi VE, Logan SD, Ashford ML. Leptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium channels. Nature. 1997;390:521–525. [PubMed: 9394003]
  99. Spanswick D, Smith MA, Mirshamsi S, Routh VH, Ashford ML. Insulin activates ATP-sensitive K+ channels in hypothalamic neurons of lean, but not obese rats. Nat Neurosci. 2000;3:757–758. [PubMed: 10903566]
  100. Stapleton D, Mitchelhill KI, Gao G, Widmer J, Michell BJ, The T, House CM, Fernandez CS, Cox T, Witters LA, Kemp BE. Mammalian AMP-activated protein kinase subfamily. J Biol Chem. 1996;271:611–614. [PubMed: 8557660]
  101. Taleux N, De Potter I, Deransart C, Lacraz G, Favier R, Leverve XM, Hue L, Guigas B. Lack of starvation-induced activation of AMP-activated protein kinase in the hypothalamus of the Lou/C rats resistant to obesity. Int J Obes (Lond). 2007;32:639–647. [PubMed: 18059408]
  102. Turton MD, O’Shea D, Gunn I, Beak SA, Edwards CM, Meeran K, Choi SJ, et al. A role for glucagon-like peptide-1 in the central regulation of feeding. Nature. 1996;379:69–72. [PubMed: 8538742]
  103. van den Hoek AM, Voshol PJ, Karnekamp BN, Buijs RM, Romijn JA, Havekes LM, Pijl H. Intracerebroventricular neuropeptide Y infusion precludes inhibition of glucose and VLDL production by insulin. Diabetes. 2004;53:2529–2534. [PubMed: 15448080]
  104. Wakil SJ, Stoops JK, Joshi VC. Fatty acid synthesis and its regulation. Ann Rev Biochem. 1983;52:537–579. [PubMed: 6137188]
  105. Williams G, Bing C, Cai XJ, Harrold JA, King PJ, Liu XH. The hypothalamus and the control of energy homeostasis—Different circuits, different purposes. Physiol Behav. 2001;74:683–701. [PubMed: 11790431]
  106. Wolfgang MJ, Lane MD. Control of energy homeostasis: Role of enzymes and intermediates of fatty acid metabolism in the central nervous system. Ann Rev Nutr. 2006;26:23–44. [PubMed: 16704352]
  107. Wolfgang MJ, Kurama T, Dai Y, Suwa A, Asaumi M, Matsumoto S, Cha SH, Shimokawa T, Lane MD. The brain-specific carnitine palmitoyltransferase-1c regulates energy homeostasis. Proc Natl Acad Sci. 2006;103:7282–7287. [PMC free article: PMC1564279] [PubMed: 16651524]
  108. Wolfgang MJ, Cha SH, Sidhaye A, Chohnan S, Cline G, Shulman GI, Lane MD. Regulation of hypothalamic malonyl-CoA by central glucose and leptin. Proc Natl Acad Sci. 2007;104:19285–19290. [PMC free article: PMC2148282] [PubMed: 18032600]
  109. Wolfgang MJ, Cha SH, Millington DS, Cline G, Shulman GI, Suwa A, Asaumi M, Kurama T, Shimokawa T, Lane MD. Brain-specific carnitine palmitoyl-transferase-1c: Role in CNS fatty acid metabolism, food intake, and body weight. J Neurochem. 2008;105:1550–1559. [PMC free article: PMC3888516] [PubMed: 18248603]
  110. Woods A, Dickerson K, Heath R, Hong SP, Momcilovic M, Johnstone SR, Carlson M, Carling D. Ca2+/calmodulin-dependent protein kinase kinase-β acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab. 2005;2:21–33. [PubMed: 16054096]
  111. Woods SC, Lotter EC, McKay LD, Porte D Jr. Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons. Nature. 1979;282:503–505. [PubMed: 116135]
  112. Woods A, Johnstone SR, Dickerson K, Leiper FC, Fryer LG, Neumann D, Schlattner U, Wallimann T, Carlson M, Carling D. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr Biol. 2003;13:2004–2008. [PubMed: 14614828]
  113. Wortman MD, Clegg DJ, D’Alessio D, Woods SC, Seeley RJ. C75 inhibits food intake by increasing CNS glucose metabolism. Nat Med. 2003;9:483–485. [PubMed: 12724740]
  114. Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, Yamashita S, et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med. 2002;8:1288–1295. [PubMed: 12368907]
Copyright © 2010, Taylor & Francis Group, LLC.
Bookshelf ID: NBK53535PMID: 21452468


  • PubReader
  • Print View
  • Cite this Page

Other titles in this collection

Related information

  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...