Brain lipogenesis and the control of food intake: the lipostatic hypothesis revisited
The classical hypothalamic neuropeptide view of feeding regulation has been extensively reviewed and revised during the last few years. Accumulating evidence indicate that pharmacological and genetic modulation of lipogenesis de novo in the hypothalamus, through selective pharmacologic and genetic manipulation of acetyl-CoA carboxylase (ACC), AMP-activated protein kinase (AMPK), carnitine palmitoyltransferase-1 (CPT1), fatty acid synthase (FAS) and malonyl-CoA decarboxylase (MCD) enzymes, has a severe impact on food intake and body weight homeostasis. Furthermore, since these manipulations alter the hypothalamic pool of lipids, such as malonyl-CoA and/or long chain fatty acids-CoA (LCFAs-CoA), the concept of lipids as signals of nutrient abundance able to modulate feeding in the hypothalamus has recently re-emerged.
Despite these pharmacological and genetic data, confirmation that it is a physiologically relevant regulatory system of feeding is still incomplete. Our current investigations have revealed that hypothalamic FAS, AMPK and CPT-1 expression and activities are modulated by peripheral signals regulating feeding, specifically in the ventromedial nucleus of the hypothalamus (VMH). Our data also identify the fatty acid biosynthetic pathway in the VMH as a potentially important physiological mediator of feeding behaviour of relevance for the understanding and treatment of obesity.