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Mol Metab. 2018 May;11:33-46. doi: 10.1016/j.molmet.2018.03.008. Epub 2018 Mar 21.

Loss of dorsomedial hypothalamic GLP-1 signaling reduces BAT thermogenesis and increases adiposity.

Author information

1
Physiology and Behavior Laboratory, ETH Zürich, 8603 Schwerzenbach, Switzerland. Electronic address: shin-lee@ethz.ch.
2
Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA.
3
Physiology and Behavior Laboratory, ETH Zürich, 8603 Schwerzenbach, Switzerland.
4
Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

Abstract

OBJECTIVE:

Glucagon-like peptide-1 (GLP-1) neurons in the hindbrain densely innervate the dorsomedial hypothalamus (DMH), a nucleus strongly implicated in body weight regulation and the sympathetic control of brown adipose tissue (BAT) thermogenesis. Therefore, DMH GLP-1 receptors (GLP-1R) are well placed to regulate energy balance by controlling sympathetic outflow and BAT function.

METHODS:

We investigate this possibility in adult male rats by using direct administration of GLP-1 (0.5 ug) into the DMH, knocking down DMH GLP-1R mRNA with viral-mediated RNA interference, and by examining the neurochemical phenotype of GLP-1R expressing cells in the DMH using in situ hybridization.

RESULTS:

GLP-1 administered into the DMH increased BAT thermogenesis and hepatic triglyceride (TG) mobilization. On the other hand, Glp1r knockdown (KD) in the DMH increased body weight gain and adiposity, with a concomitant reduction in energy expenditure (EE), BAT temperature, and uncoupling protein 1 (UCP1) expression. Moreover, DMH Glp1r KD induced hepatic steatosis, increased plasma TG, and elevated liver specific de-novo lipogenesis, effects that collectively contributed to insulin resistance. Interestingly, DMH Glp1r KD increased neuropeptide Y (NPY) mRNA expression in the DMH. GLP-1R mRNA in the DMH, however, was found in GABAergic not NPY neurons, consistent with a GLP-1R-dependent inhibition of NPY neurons that is mediated by local GABAergic neurons. Finally, DMH Glp1r KD attenuated the anorexigenic effects of the GLP-1R agonist exendin-4, highlighting an important role of DMH GLP-1R signaling in GLP-1-based therapies.

CONCLUSIONS:

Collectively, our data show that DMH GLP-1R signaling plays a key role for BAT thermogenesis and adiposity.

KEYWORDS:

Adipose tissue; Hypothalamus; Neuropeptide; Obesity; Sympathetic nerve

PMID:
29650350
PMCID:
PMC6001878
DOI:
10.1016/j.molmet.2018.03.008
[Indexed for MEDLINE]
Free PMC Article

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