Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase

Abstract

Leptin is a hormone secreted by adipocytes that plays a pivotal role in regulating food intake, energy expenditure and neuroendocrine function. Leptin stimulates the oxidation of fatty acids and the uptake of glucose, and prevents the accumulation of lipids in nonadipose tissues, which can lead to functional impairments known as "lipotoxicity". The signalling pathways that mediate the metabolic effects of leptin remain undefined. The 5'-AMP-activated protein kinase (AMPK) potently stimulates fatty-acid oxidation in muscle by inhibiting the activity of acetyl coenzyme A carboxylase (ACC). AMPK is a heterotrimeric enzyme that is conserved from yeast to humans and functions as a 'fuel gauge' to monitor the status of cellular energy. Here we show that leptin selectively stimulates phosphorylation and activation of the alpha2 catalytic subunit of AMPK (alpha2 AMPK) in skeletal muscle, thus establishing a previously unknown signalling pathway for leptin. Early activation of AMPK occurs by leptin acting directly on muscle, whereas later activation depends on leptin functioning through the hypothalamic-sympathetic nervous system axis. In parallel with its activation of AMPK, leptin suppresses the activity of ACC, thereby stimulating the oxidation of fatty acids in muscle. Blocking AMPK activation inhibits the phosphorylation of ACC stimulated by leptin. Our data identify AMPK as a principal mediator of the effects of leptin on fatty-acid metabolism in muscle.

Long‐lived hypopituitary Ames dwarf mice are resistant to the detrimental effects of high‐fat diet on metabolic function and energy expenditure

“…We observed high levels of NEFAs in Ames dwarf mice fed HFD compared to Ames dwarf fed STD and control mice fed either diet. We could only assume that intracellular signaling in peripheral tissues aided the breakdown of triglycerides into NEFAs to be utilized as energy substrates (Minokoshi et al ., 2002) preserving glucose homeostasis in Ames dwarf mice fed HFD, as observed in our ITT and GTT data.…”

“…Leptin bound to its receptor induces Janus activating kinase/signal transducer and activator of transcription , mitogen‐activated protein kinase, phosphatidylinsitol 3′kinase , and AMP‐activated protein kinase (AMPK) (Vozarova et al ., 2001). Activation of the AMPK pathway stimulates glucose uptake (Kurth‐Kraczek et al ., 1999) and lipid oxidation (Minokoshi et al ., 2002) to produce energy while simultaneously reduces energy consuming processes (Friedman & Halaas, 1998). This regulation of energy metabolism takes place in multiple peripheral tissues including skeletal muscle, liver, adipose tissues, and pancreatic beta cells which all function in either insulin sensitivity or insulin resistance.…”

Substrate cycling between de novo lipogenesis and lipid oxidation: a thermogenic mechanism against skeletal muscle lipotoxicity and glucolipotoxicity

“…A requirement for AMPK activation and for entry of fatty acids through the mitochondrial b-oxidation pathway was also suggested by the fact that leptin-induced thermogenesis was inhibited either in the presence of araA (an inhibitor of AMPK) or by addition of etomoxir, an inhibitor of CPT-1. 63 In other experiments that involved interference with key control points of intermediary metabolism in order to investigate the nature of an 'apparent' link between leptin's direct effects on skeletal muscle to stimulate glucose metabolism, 58-60 lipid oxidation [57][58][59][60][61] and thermogenesis, 62 evidence emerged of a requirement for de novo lipogenesis in the mechanism by which leptin stimulates muscle thermogenesis. 63 Specifically, the direct thermogenic effect of leptin on skeletal muscle O 2 consumption was found to be completely inhibited by the addition of any one of the following compounds that would inhibit the synthesis of lipids from glucose, namely (a) 2-deoxyglucose, which interferes with glucose metabolism, (b) hydroxy-citrate, which inhibits citrate lyase and hence the conversion of citrate to acetyl-CoA and (c) cerulenin, which inhibits fatty acid synthase and hence the conversion of malonyl-CoA to fatty acids.…”

“…One can also entertain the interesting possibility that, in skeletal muscle, this substrate cycling is also activated in response to other hormones and neurotransmitters (eg, adiponectin, catecholamines) particularly since adiponectin, as well as adrenergic agonists, can also stimulate AMPK activity, glucose utilization and fatty acid oxidation in skeletal muscle or adipose tissue. 61,[66][67][68][69] This substrate cycling between de novo lipogenesis and lipid oxidation could therefore constitute a thermogenic effector in skeletal muscle. Theoretically, the synthesis of one molecule of palmitic acid from acetyl-CoA and its re-oxidation to acetylCoA would cost at least 14 molecules of ATP.…”

Body weight is regulated by the brain: a link between feeding and emotion

“…[2][3][4] On one hand, there is a possibility that antipsychotics directly influence peripheral organs per se, including pancreatic b-cells, liver, adipose tissue, and skeletal muscle, resulting in impaired glucose tolerance. 196,197 On the other hand, antipsychotics may affect CNS systems regulating glucose metabolism. The 5-HT/5-HT2cR system is one of the candidates, as several antipsychotic agents bind to 5-HT2cRs with high affinities.…”