Fatty Acid Metabolism, the Central Nervous System, and Feeding

Abstract

A potential role for fatty acid metabolism in the regulation of energy balance in the brain or in the periphery has been considered only recently. Fatty acid synthase (FAS) catalyzes the synthesis of long-chain fatty acids, whereas the breakdown of fatty acids by beta-oxidation is regulated by carnitine palmitoyltransferase-1, the rate-limiting enzyme for the entry of fatty acids into the mitochondria for oxidation. While the question of the physiological role of fatty acid metabolism remains to be resolved, studies indicate that inhibition of FAS or stimulation of carnitine palmitoyltransferase-1 using cerulenin or synthetic FAS inhibitors reduces food intake and incurs profound and reversible weight loss. Several hypotheses regarding the mechanisms by which these small molecules mediate their effects have been entertained. Centrally, these compounds alter the expression of hypothalamic neuropeptides, generally reducing the expression of orexigenic peptides. Whether through central, peripheral, or combined central and peripheral mechanisms, these compounds also increase energy consumption to augment weight loss. In vitro and in vivo studies indicate that at least part of C75's effects is mediated by modulation of adenosine monophosphate-activated protein kinase, a member of an energy-sensing kinase family. These compounds, with chronic treatment, also alter gene expression peripherally to favor a state of enhanced energy consumption. Together, these effects raise the possibility that pharmacological alterations in fatty acid synthesis/degradation may serve as a target for obesity therapeutics.

The Role of Hypothalamic H1 Receptor Antagonism in Antipsychotic-Induced Weight Gain

“…[51,53,55,60] Hypothalamic AMPK regulates fatty acid metabolism pathways in the CNS and plays an important role in feeding regulation and energy homeostasis, although the CNS does not use fatty acids as a primary energy source (reviewed in [68,74] ). Both genetic and pharmacological modifications of the key steps of AMPK-regulated fatty acid metabolism affect food intake and body weight (AMPK-ACC-Malonyl-CoA-CPT1 axis; ACC: acetyl-CoA carboxylase;…”

Fatty acid synthase gene regulation in primary hypothalamic neurons

“…It has been hypothesized that fatty acid metabolic pathways contribute to the regulation of energy balance and metabolic homeostasis by distinct mechanisms in the hypothalamus [17]. C75, a synthetic fatty acid synthase (FAS) inhibitor and carnitine palmitoyltransferase-1 (CPT-1) stimulator, causes anorexia by modulating gene expression of neuropeptides in the hypothalamus of lean, diet-induced obese (DIO) and ob/ob mice, leading to weight loss [11,13,22,23].…”

Central lipid detection and the regulation of feeding behavior

“…The two components integrate several circulating factors of hunger and satiety and communicate with one another to adapt both metabolic demands and the hedonic and motivational aspect of food intake. Although it is generally accepted that the brain does not uses lipids as a primary source of energy, it expresses several enzymes involved in the transport, hydrolysis and manipulation of TG-rich particle and LCFAs (Kim et al, 2002;Ronnett et al, 2005;Ronnett et al, 2006). Central LCFAs sensing in the hypothalamus was recently demonstrated to be a key mechanism for the homeostatic regulation of food intake Migrenne et al, 2011).…”

“…Elevated circulating levels of long-chain fatty acids (LCFAs), which are often elevated in obese and diabetic individuals, have recently been demonstrated to be an important signaling molecule acting in the hypothalamus to control food intake and energy expenditure (Kim et al, 2002;Ronnett et al, 2005;Ronnett et al, 2006). In addition, component of the reward circuitry also expresses several enzymes involved in the processing of triglyceride and fatty acid including lipoprotein lipase (LPL) (Ben-Zeev et al, 1990;Paradis et al, 2004), an enzyme responsible for triglyceride hydrolysis.…”