Energetic and biosynthetic functions of de novo lipogenesis (DNL) in the control of metabolic homeostasis. (A) DNL produces lipids by disposing of glucose and calories. Whereas lipids can be directly incorporated into intracellular stores in an energetically efficient manner, the conversion of glucose into intracellular lipids via DNL is a costly process. Glucose enters the cell via specific glucose transporters. It is converted to pyruvate via glycolysis and, in this form, enters the mitochondria where it is converted to acetyl-CoA in order to enter the Krebs cycle. In the presence of excessive glucose and calories, citrate from the Krebs cycle is exported to the cytoplasm via the citrate carrier (CIC). The latter is the first committed step of DNL. Indeed, citrate is a powerful inducer of acetyl-CoA carboxylase (ACC) activity, which produces malonyl-CoA, a major intermediate of fatty acid synthesis and an inhibitor of the fatty acid transporter CPT-1. However, it is important to consider that fatty acid synthase (FAS) consumes malonyl-CoA, limiting its accumulation and consequent inhibition of CPT-1. Because DNL and β-oxydation of fatty acids are distinct pathways, fatty acid synthesis and β-oxidation can occur simultaneously, creating futile cycles as described during brown adipose tissue activation and browning of white adipose tissue. The pentose phosphate pathway (PPP) is an important intracellular source of NADPH, which provides energy for DNL. Altogether DNL is an energetically inefficient way to form intracellular lipids and, in specific circumstances, can act as a considerable sink for calories and glucose. (B) DNL was also proposed to support the synthesis of several signaling molecules implicated in the control of metabolic homeostasis. These include specific lipids of the sarcoplasmic reticulum (SR) membrane controlling SERCA function and intracellular calcium; secreted lipids with cytokine-like activity supporting metabolic homeostasis “lipokines”, such as palmitoleic acid (PAO) and branched fatty acid esters of hydroxy fatty acids (FAHFA); endogenous ligands of nuclear receptors including PPARα (16:0/18:1-GPC), PPARγ (alkyl ether lipids), and possibly LXR. DNL was also implicated in the palmitoylation and acetylation of specific proteins.