Hypothalamic malonyl-CoA and the control of food intake

Abstract

Fatty acid metabolism is implicated in the hypothalamic control of food intake. In this regard, malonyl-CoA, an intermediate in fatty acid synthesis, is emerging as a key player. Malonyl-CoA in the hypothalamus has been proposed as an anorectic mediator in the central control of feeding. A large body of evidence demonstrates that modulating hypothalamic activities of malonyl-CoA metabolic enzymes impacts food intake. Malonyl-CoA action appears to play a significant role in the intracellular signaling pathways underlying leptin anorectic effect in the arcuate nucleus. Ghrelin's hypothalamic effect on feeding may also involve the change in malonyl-CoA metabolism. Hypothalamic malonyl-CoA levels are altered in response to fasting and refeeding, suggesting physiological relevance of the changes in malonyl-CoA level in the controls of feeding and energy balance. Malonyl-CoA inhibits the acyltransferase activity of carnitine palmitoyltransferase-1 (CPT-1), and CPT-1 was considered as a downstream effector in hypothalamic malonyl-CoA effect on feeding. However, recent evidence has not been entirely consistent with this notion. In the arcuate nucleus, the inhibition of CPT-1 acyltransferase activity does not play an important role in the feeding effect of either leptin or cerulenin (a fatty acid synthase inhibitor) that requires the increase in malonyl-CoA level. Alternatively, the brain isoform of CPT-1 (CPT-1c) may act as a downstream target in the malonyl-CoA signaling pathways. CPT-1c does not possess a typical acyltransferase activity, and the exact molecular function of this protein is currently unknown. Recent data indicate it is involved in ceramide metabolism. Of relevance, in the arcuate nucleus, CPT-1c may link malonyl-CoA to ceramide metabolism to affect food intake.

Keywords: Carnitine palmitoyltransferase; Fatty acid; Food intake; Hypothalamus; Malonyl-CoA.

Fig. 1

Acetyl-CoA, derived from glucose metabolism, is converted to malonyl-CoA by acetyl-CoA carboxylase (ACC). Malonyl-CoA is incorporated by fatty acid synthase (FAS) into long-chain fatty acid such as palmitic acid, or is degraded to acetyl-CoA by malonyl-CoA decarboxylase (MCD).

Fig. 2

Malonyl-CoA in the hypothalamus is proposed as an anorectic mediator in the CNS control of food intake. Leptin inhibits AMP-activated kinase (AMPK) that inhibits ACC. This leads to activation of ACC resulting in increase in malonyl-CoA level. Glucose activates ACC by inhibiting AMPK, and increases availability of acetyl-CoA. Both effects result in increases in malonyl-CoA level. FAS inhibitors such as C75 and cerulenin, deletion of FAS protein, and tamoxifen that downregulates FAS level, increase malonyl-CoA levels. MCD inhibitor (MCDi) reduces MCD activity resulting in increase in malonyl-CoA level. The increases in malonyl-CoA level lead to decrease in food intake. Overexpression of MCD reduces malonyl-CoA level, which leads to increase in food intake. Antisense oligonucleotide reduces ACC protein level decreasing malonyl-CoA level, which increases food intake.

Fig. 3

(A) Fasting: Some rats were fasted for around 24 h (fasted, n = 10). The other rats were fed ad lib. (fed, n = 12). (B) Refeeding: Some rats were fasted for around 48 h (fasted, n = 12). The other rats were presented with food at the end of fasting (refed, n = 11). The mediobasal hypothalamus consisting mainly of the Arc nucleus was dissected. Phospho-AMPK (pThr 172), phospho-ACC (pSer79), AMPK (α-subunit) and ACC (α-isoform) were measured by Western blotting analysis. The level of phospho-AMPK (pAMPK) or phospho-ACC (pACC) was normalized to that of AMPK or ACC. Actin was used as the loading control. ACC activity assay was performed based on the method of ¹⁴CO₂ fixation to acid-stable products as described in Reference [29].

Fig. 4

In the Arc nucleus, CPT-1c and ceramide de novo biosynthesis mediates downstream effect of malonyl-CoA action on feeding. Malonyl-CoA may inhibit CPT-1c function, and CPT-1c regulates ceramide level, possibly by enhancing de novo biosynthesis. Leptin and cerulenin that increase the levels of malonyl-CoA would inhibit CPT-1c, which leads to decreases in ceramide level. The reduction of ceramide level is involved in the decrease in food intake. In contrast, MCD overexpression reducing the malonyl-CoA level would activate CPT-1c, which leads to increase in ceramide level. The upregulation of ceramide level contributes to the increase in food intake.