Metabolic integration of nutrient sensing in the central nervous system has been shown to be an important regulator of adiposity by affecting food intake and peripheral energy expenditure. Modulation of de novo
fatty acid synthetic flux by
cytokines and nutrient availability plays an important role in this process. Inhibition of hypothalamic
fatty acid synthase by pharmacologic or genetic means leads to an increased
malonyl-CoA level and suppression of food intake and adiposity. Conversely, the ectopic expression of
malonyl-CoA decarboxylase in the hypothalamus is sufficient to promote feeding and adiposity. Based on these and other findings, metabolic intermediates in
fatty acid biogenesis, including
malonyl-CoA and long-chain acyl-CoAs, have been implicated as signaling mediators in the central control of
body weight.
Malonyl-CoA has been hypothesized to mediate its effects in part through an allosteric interaction with an atypical and brain-specific
carnitine palmitoyltransferase-1 (CPT1c). CPT1c is expressed in neurons and binds
malonyl-CoA, however, it does not perform the same biochemical function as the prototypical CPT1
enzymes. Mouse knockout models of CPT1c exhibit suppressed food intake and smaller
body weight, but are highly susceptible to
weight gain when fed a high-fat diet. Thus, the brain can directly sense and respond to changes in nutrient availability and composition to affect
body weight and adiposity.