ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2006) 12 S26

Central and peripheral effects of leptin on AMP-activated protein kinase

Y Minokoshi

National Institute for Physiological Sciences, Okazaki, Japan.

AMP-activated protein kinase (AMPK) is a serine/threonine kinase which is evolutionally conserved from yeast to humans and is expressed in virtually all cell types including muscle, neurons and glial cells. We previously demonstrated that AMPK plays an important role in the regulation of peripheral intermediate metabolism by adipocytokines such as leptin and adiponectin, and that hypothalamic AMPK regulates food intake by responding to hormonal and nutrient signals. Our data indicate that leptin stimulates fatty acid oxidation in skeletal muscle by activating AMPK. Leptin exerts this effect directly at the level of muscle and through the hypothalamic-sympathetic nervous system. In contrast, hypothalamic AMPK activity is inhibited by anorexigenic hormones such as leptin and insulin, high glucose and refeeding. Leptin decreases AMPK activity in the paraventricular (PVH) and arcuate (ARH) hypothalamus preferentially.

We recently examined the chronic effects of constitutively-active (CA) AMPK in the paraventricular hypothalamus (PVH) on food intake in mice, by using lenti-virus. CA-AMPK [alpha1(1-312)T172D] in the PVH neurons increased food intake and body weight without any change in the diurnal/nocturnal rhythm. The body weight reached about 45 g 3 months after the virus injection, while the control was less than 35 g.

We also explored the signaling pathway of leptin’s effects on AMPK activity in C2C12 muscle cell and SH-SY5Y neuronal cell lines. Leptin increased fatty acid oxidation in C2C12 cells through activation of alpha2 AMPK. The activation is mediated by ataxia-telangiectasia mutated (ATM) and calcium/calmodulin-dependent protein kinase kinase beta (CaMKKbeta). Furthermore, leptin involved the induction of CaMKKbeta gene expression in PI3-kinase-dependent manner. In contrast, leptin suppressed alpha2 AMPK activity in SH-SY5Y cells.

Thus, leptin regulates AMPK activity in neuronal and muscle cells reciprocally. The reciprocal regulation of AMPK activity plays a critical role in the peripheral and central effects of leptin.

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