The AMP-activated protein kinase (AMPK) is an evolutionarily conserved sensor of cellular energy status, and recent data demonstrate that it also plays a critical role in systemic energy balance. AMPK integrates nutritional and hormonal signals in peripheral tissues and the hypothalamus. It mediates effects of adipokines (leptin, adiponectin, and possibly resistin) in regulating food intake, body weight, and glucose and lipid homeostasis. AMPK is regulated by upstream kinases of which the tumor suppressor, LKB1, is the first to be identified. Complex signaling networks suggest that AMPK may prevent insulin resistance, in part by inhibiting pathways that antagonize insulin signaling. Through signaling, metabolic, and gene expression effects, AMPK enhances insulin sensitivity and fosters a metabolic milieu that may reduce the risk for obesity and type 2 diabetes.

Obesity is an epidemic in Western society, and causes rapidly accelerating rates of type 2 diabetes and cardiovascular disease. The evolutionarily conserved serine/threonine kinase, AMP-activated protein kinase (AMPK), functions as a 'fuel gauge' to monitor cellular energy status. We investigated the potential role of AMPK in the hypothalamus in the regulation of food intake. Here we report that AMPK activity is inhibited in arcuate and paraventricular hypothalamus (PVH) by the anorexigenic hormone leptin, and in multiple hypothalamic regions by insulin, high glucose and refeeding. A melanocortin receptor agonist, a potent anorexigen, decreases AMPK activity in PVH, whereas agouti-related protein, an orexigen, increases AMPK activity. Melanocortin receptor signalling is required for leptin and refeeding effects on AMPK in PVH. Dominant negative AMPK expression in the hypothalamus is sufficient to reduce food intake and body weight, whereas constitutively active AMPK increases both. Alterations of hypothalamic AMPK activity augment changes in arcuate neuropeptide expression induced by fasting and feeding. Furthermore, inhibition of hypothalamic AMPK is necessary for leptin's effects on food intake and body weight, as constitutively active AMPK blocks these effects. Thus, hypothalamic AMPK plays a critical role in hormonal and nutrient-derived anorexigenic and orexigenic signals and in energy balance.

Long-chain fatty acids amplify insulin secretion from the pancreatic beta cell. The G protein-coupled receptor GPR40 is specifically expressed in beta cells and is activated by fatty acids. Loss of function of GPR40 was shown to markedly inhibit fatty-acid stimulation of insulin secretion in vitro. However, the role of GPR40 in acute regulation of insulin secretion in vivo remains unclear. To this aim, we generated GPR40 knock-out (KO) mice and examined glucose homeostasis, insulin secretion in response to glucose and Intralipid in vivo, and insulin secretion in vitro after short-and long-term exposure to fatty acids. Our results show that GPR40 KO mice have essentially normal glucose tolerance and insulin secretion in response to glucose. Insulin secretion in response to Intralipid was reduced by approximately 50%. In isolated islets, insulin secretion in response to glucose and other secretagogues was unaltered, but fatty-acid potentiation of insulin release was markedly reduced. Islets from GPR40 KO mice were as sensitive to fatty-acid inhibition of insulin secretion upon prolonged exposure as islets from wild-type animals. We conclude that GPR40 contributes approximately half of the full insulin secretory response to fatty acids in mice, but does not play a role in the mechanisms of lipotoxicity.Long-chain fatty acids are essential regulators of normal pancreatic beta-cell function, and are likely to play a role in the pathogenesis of beta-cell dysfunction in type 2 diabetes (reviewed in (1)). Under normal circumstances, fatty acids do not initiate insulin release, but amplify glucose-stimulated insulin secretion (GSIS) (2-5). Fatty-acid potentiation of insulin secretion has physiological implications, particularly after a period of fasting (6). Until recently, the prevailing model postulated that the effects of fatty acids on the beta cell were mediated by their intracellular metabolism and the generation of lipid derived signals which, in turn, potentiate GSIS (2;7). According to this hypothesis, fatty acids are transported across the plasma membrane and activated into their long-chain coenzyme A esters, which in turn modulate a number of intracellular targets that influence insulin secretion. Moreover, evidence suggests that intracellular fatty-acid metabolism is a key component of both nutrient-and nonnutrient-induced insulin secretion (7). In contrast to their acute, stimulatory effect on GSIS, prolonged exposure to elevated levels of fatty acids impairs beta-cell function, a phenomenon referred to as lipotoxicity (reviewed in (1)). The mechanisms of lipotoxicity remain poorly understood but have been proposed to also involve intracellular metabolism of fatty acids and the generation of lipid-derived metabolites (8).The models described above have been challenged by the observation that fatty acids activate the G-protein coupled receptor (GPCR) GPR40 (9-11), also referred to as the free fatty-acid 1 receptor (FFA 1 R) (12;13). GPR40 belongs to a class of GPCR with high structural conservation, o...