Adiponectin, an adipocyte-derived hormone, regulates glucose and lipid metabolism. It is also antiinflammatory. During obesity, adiponectin levels and sensitivity are reduced. Whereas the action of adiponectin in the periphery is well established the neuroendocrine role of adiponectin is largely unknown. To address this we analyzed the expression of adiponectin and the 2 adiponectin receptors (AdipoR1 and AdipoR2) in response to fasting and to diet-induced and genetic obesity. We also investigated the acute impact of adiponectin on central regulation of glucose homeostasis. Adiponectin (1 μg) was injected intracerebroventricularly (ICV), and glucose tolerance tests were performed in dietary and genetic obese mice. Finally, the influence of ICV adiponectin administration on central signaling cascades regulating glucose homeostasis and on markers of hypothalamic inflammation was assessed. Gene expression of adiponectin was down-regulated whereas AdipoR1 was up-regulated in the arcuate nucleus of fasted mice. High-fat (HF) feeding increased AdipoR1 and AdipoR2 gene expression in this region. In mice on a HF diet and in leptin-deficient mice acute ICV adiponectin improved glucose tolerance 60 minutes after injection, whereas normoglycemia in control mice was unaffected. ICV adiponectin increased pAKT, decreased phospho-AMP-activated protein kinase, and did not change phospho-signal transducer and activator of transcription 3 immunoreactivity. In HF-fed mice, ICV adiponectin reversed parameters of hypothalamic inflammation and insulin resistance as determined by the number of phospho-glycogen synthase kinase 3 β(Ser9) and phospho-c-Jun N-terminal kinase (Thr183/Tyr185) immunoreactive cells in the arcuate nucleus and ventromedial hypothalamus. This study demonstrates that the insulin-sensitizing properties of adiponectin are at least partially based on a neuroendocrine mechanism that involves centrally synthesized adiponectin.

The occurrence of type II diabetes is highly correlated with obesity, but the mechanisms linking both conditions are incompletely understood. Leptin is a potent insulin sensitizer and in leptin deficient, insulin insensitive Lep ob/ob mice leptin improves glucose tolerance. Leptin resistance naturally occurs in response to a high fat diet (HFD) and both hyperleptinemia and inflammation have been proposed as causative mechanisms. Since Lep ob/ob mice are highly sensitive to leptin the possibility that leptin could reverse HFD-induced glucose intolerance in these animals was investigated. Peripherally administered leptin improved glucose tolerance and reduced food intake in Lep ob/ob mice on control diet (CD), but was ineffective in HFD-fed mice. Central administration significantly impaired glucose tolerance of Lep ob/ob mice on HFD. While, as expected, leptin induced the number of phospho-STAT3 immunoreactive cells in the ARC of Lep ob/ob mice on CD, HFD was associated with maximal phospho-STAT3 activation that was unaffected by leptin administration, suggesting central leptin resistance. Negating hypothalamic inflammation by co-administering a JNK inhibitor reinstated the glucose lowering effects of leptin, indicating that JNK signalling is involved in the induction of diet-induced glucose intolerance. Together these findings show that HFD-fed Lep ob/ob mice develop leptin resistance independent of hyperleptinemia.

Obesity is associated with resistance to the actions of both leptin and insulin via mechanisms that remain incompletely understood. To investigate whether leptin resistance per se contributes to insulin resistance and impaired glucose homeostasis, we investigated the effect of acute leptin administration on glucose homeostasis in normal as well as leptin- or leptin receptor-deficient mice. In hyperglycemic, leptin-deficient Lepob/obmice, leptin acutely and potently improved glucose metabolism, before any change of body fat mass, via a mechanism involving the p110α and β isoforms of phosphatidylinositol-3-kinase (PI3K). Unlike insulin, however, the anti-diabetic effect of leptin occurred independently of phospho-AKT, a major downstream target of PI3K, and instead involved enhanced sensitivity of the hypothalamus to insulin action upstream of PI3K, through modulation of IRS1 (insulin receptor substrate 1) phosphorylation. These data suggest that leptin resistance, as occurs in obesity, reduces the hypothalamic response to insulin and thereby impairs peripheral glucose homeostasis, contributing to the development of type 2 diabetes.