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Objective: The medial hypothalamus mediates leptin-induced glucose uptake in peripheral tissues, and brain melanocortin receptors (MCRs) mediate certain central effects of leptin. However, the contributions of the leptin receptor and MCRs in individual medial hypothalamic nuclei to regulation of peripheral glucose uptake have remained unclear. We examined the effects of an injection of leptin and the MCR agonist MT-II into medial hypothalamic nuclei on glucose uptake in peripheral tissues., Research Design and Methods: Leptin or MT-II was injected into the ventromedial (VMH), dorsomedial (DMH), arcuate nucleus (ARC), or paraventricular (PVH) hypothalamus or the lateral ventricle (intracerebroventricularly) in freely moving mice. The MCR antagonist SHU9119 was injected intracerebroventricularly. Glucose uptake was measured by the 2-[(3)H]deoxy-d-glucose method., Results: Leptin injection into the VMH increased glucose uptake in skeletal muscle, brown adipose tissue (BAT), and heart, whereas that into the ARC increased glucose uptake in BAT, and that into the DMH or PVH had no effect. SHU9119 abolished these effects of leptin injected into the VMH. Injection of MT-II either into the VMH or intracerebroventricularly increased glucose uptake in skeletal muscle, BAT, and heart, whereas that into the PVH increased glucose uptake in BAT, and that into the DMH or ARC had no effect., Conclusions: The VMH mediates leptin- and MT-II-induced glucose uptake in skeletal muscle, BAT, and heart. These effects of leptin are dependent on MCR activation. The leptin receptor in the ARC and MCR in the PVH regulate glucose uptake in BAT. Medial hypothalamic nuclei thus play distinct roles in leptin- and MT-II-induced glucose uptake in peripheral tissues.

Leptin stimulates fatty acid oxidation in skeletal muscle through the activation of AMP-activated protein kinase (AMPK) and the induction of gene expression, such as that for peroxisome proliferator-activated receptor alpha (PPARalpha). We now show that leptin stimulates fatty acid oxidation and PPARalpha gene expression in the C2C12 muscle cell line through the activation of AMPK containing the alpha2 subunit (alpha2AMPK) and through changes in the subcellular localization of this enzyme. Activated alpha2AMPK containing the beta1 subunit was shown to be retained in the cytoplasm, where it phosphorylated acetyl coenzyme A carboxylase and thereby stimulated fatty acid oxidation. In contrast, alpha2AMPK containing the beta2 subunit transiently increased fatty acid oxidation but underwent rapid translocation to the nucleus, where it induced PPARalpha gene transcription. A nuclear localization signal and Thr(172) phosphorylation of alpha2 were found to be essential for nuclear translocation of alpha2AMPK, whereas the myristoylation of beta1 anchors alpha2AMPK in the cytoplasm. The prevention of alpha2AMPK activation and the change in its subcellular localization inhibited the metabolic effects of leptin. Our data thus suggest that the activation of and changes in the subcellular localization of alpha2AMPK are required for leptin-induced stimulation of fatty acid oxidation and PPARalpha gene expression in muscle cells.

Leptin stimulates fatty acid oxidation in skeletal muscle through the activation of AMP-activated protein kinase (AMPK) and the induction of gene expression, such as that for peroxisome proliferator-activated receptor α (PPAR α). We now show that leptin stimulates fatty acid oxidation and PPAR α gene expression in the C2C12 muscle cell line through the activation of AMPK containing the α 2 subunit (α 2AMPK) and through changes in the subcellular localization of this enzyme. Activated α 2AMPK containing the β1 subunit was shown to be retained in the cytoplasm, where it phosphorylated acetyl coenzyme A carboxylase and thereby stimulated fatty acid oxidation. In contrast, α 2AMPK containing the β2 subunit transiently increased fatty acid oxidation but underwent rapid translocation to the nucleus, where it induced PPAR α gene transcription. A nuclear localization signal and Thr172 phosphorylation of α 2 were found to be essential for nuclear translocation of α 2AMPK, whereas the myristoylation of β1 anchors α 2AMPK in the cytoplasm. The prevention of α 2AMPK activation and the change in its subcellular localization inhibited the metabolic effects of leptin. Our data thus suggest that the activation of and changes in the subcellular localization of α 2AMPK are required for leptin-induced stimulation of fatty acid oxidation and PPAR α gene expression in muscle cells. [ABSTRACT FROM AUTHOR]

The hypothalamic AMP-kinase regulates feeding behavior in response to hormonal and nutrient signals. Decrease of AMP-kinase activity in the paraventricular (PVH) and arcuate hypothalamus plays an important role in anorexic effect of leptin. However, the effect of AMP-kinase on long-term energy balance remains to be established. In the present study, we examined the effect of chronic expression of constitutively-active AMP-kinase (CA-AMPK) in the PVH on food intake and body weight in male C57/BL6 mice, using lenti-viral vector with synapsin 1 promotor. CA-AMPK in the PVH significantly increased body weight (CA-AMPK mice: 11.0 ± 1.5 g vs. the control mice: 3.5 ± 0.3 g, during 3 months after the infection). CA-AMPK mice also increased food intake before the increase in body weight (CA-AMPK mice: 14.8 ± 0.9 kcal vs. control mice: 12.9 ± 0.1 kcal/day, I month after the infection). Interestingly, CA-AMPK mice increased food intake only under high carbohydrate diet (lob chow or high sucrose diet) but not under high fat diet (60% Fat). In contrast, the control mice increased the intake of high fat diet but not high carbohydrate diet (intake of high fat diet in CA-AMPK mice: 11.7 ± 0.9 kcal and in the control mice: 16.5 ± 0.9 kcal/day). When both high sucrose and high fat diets were simultaneously available, CA-AMPK mice chose high sucrose diet, whereas the control mice chose high fat diet. CA-AMPK increased the mRNA expression of fatty acid oxidation-related genes in the PVH such as PPAR alpha, FATP1, acyl-CoA synthetase 1 and CPT1c. Direct administration of etomoxir, an inhibitor of CPT-1 and fatty acid oxidation in mitochondria, into the PVH in the CA-AMPK mice, reversed to the high preference for high fat diet. Thus, these findings suggest that AMP-kinase in the PVH regulates not only calorie intake but also the preference for carbohydrate and fat diets. AMP-kinase in the PVH may control the food preference by changing fatty acid metabolism in the nucleus. [ABSTRACT FROM AUTHOR]

Abstract: Adenosine monophosphate–activated protein kinase (AMPK) functions as a cellular fuel gauge that regulates metabolic pathways in nutrient metabolism. Recent studies have strongly implicated that AMPK in the hypothalamus regulates energy metabolism by integrating inputs from multiple hormones, peptides, neurotransmitters, and nutrients. Leptin is an adipocyte hormone that regulates food intake and energy expenditure in peripheral tissues. Leptin inhibits AMPK activity in the arcuate and paraventricular hypothalamus, and its inhibition is necessary for the anorexic effect of leptin. Alteration of hypothalamic AMPK activity is sufficient to change food intake and body weight. Furthermore, fasting/refeeding, glucose, and melanocortin receptor alter AMPK activity in the hypothalamus. Adiponectin has also been shown to increase food intake by activating AMPK in the arcuate hypothalamus. Recent data have shown that acetyl-coenzyme A carboxylase/malonyl-coenzyme A/carnitine palmitoyltransferase-1/fatty acid oxidation and mammalian target of rapamycin signalings are putative downstream pathways for food intake regulation in response to hypothalamic AMPK. Thus, these results suggest that food intake and nutrient metabolism are coordinately regulated by the common signaling pathway of AMPK in the hypothalamus. [Copyright &y& Elsevier]