Hypothalamic leptin signalling has a key role in food intake and energy-balance control and is often impaired in obese individuals. Here we identify histone deacetylase 5 (HDAC5) as a regulator of leptin signalling and organismal energy balance. Global HDAC5 KO mice have increased food intake and greater diet-induced obesity when fed high-fat diet. Pharmacological and genetic inhibition of HDAC5 activity in the mediobasal hypothalamus increases food intake and modulates pathways implicated in leptin signalling. We show HDAC5 directly regulates STAT3 localization and transcriptional activity via reciprocal STAT3 deacetylation at Lys685 and phosphorylation at Tyr705. In vivo, leptin sensitivity is substantially impaired in HDAC5 loss-of-function mice. Hypothalamic HDAC5 overexpression improves leptin action and partially protects against HFD-induced leptin resistance and obesity. Overall, our data suggest that hypothalamic HDAC5 activity is a regulator of leptin signalling that adapts food intake and body weight to our dietary environment.

Background: Upon entering the pancreatic ␤-cell, glucose is metabolized to ultimately induce both proliferation and the release of insulin. Results: miR-184 targets Argonaute2 to impact the microRNA pathway according to glucose metabolism. Conclusion: miR-184 is a highly regulated microRNA impacting the growth and function of the ␤-cell. Significance: These results highlight the adaptive role of the microRNA pathway based on metabolic state.

In pancreatic b-cells, mitochondrial bioenergetics control glucose-stimulated insulin secretion. Mitochondrial dynamics are generally associated with quality control, maintaining the functionality of bioenergetics. By acute pharmacological inhibition of mitochondrial fission protein Drp1, we demonstrate in this study that mitochondrial fission is necessary for glucose-stimulated insulin secretion in mouse and human islets. We confirm that genetic silencing of Drp1 increases mitochondrial proton leak in MIN6 cells. However, our comprehensive analysis of pancreatic islet bioenergetics reveals that Drp1 does not control insulin secretion via its effect on proton leak but instead via modulation of glucose-fueled respiration. Notably, pyruvate fully rescues the impaired insulin secretion of fission-deficient b-cells, demonstrating that defective mitochondrial dynamics solely affect substrate supply upstream of oxidative phosphorylation. The present findings provide novel insights into how mitochondrial dysfunction may cause pancreatic b-cell failure. In addition, the results will stimulate new thinking in the intersecting fields of mitochondrial dynamics and bioenergetics, as treatment of defective dynamics in mitochondrial diseases appears to be possible by improving metabolism upstream of mitochondria.The development of type 2 diabetes is associated with mitochondrial dysfunction in pancreatic b-cells. b-Cells have developed highly coordinated mechanisms that link glucose sensing with metabolic signaling cascades that direct the secretion of sufficient insulin to maintain glucose homeostasis (1). The mechanism underlying glucose-stimulated insulin secretion (GSIS) from b-cells involves glucose uptake by specific glucose transporters followed by glucose catabolism through glycolysis yielding pyruvate, which in turn is further catabolized via the tricarboxylic acid cycle. Both glycolysis and tricarboxylic acid cycle turnover generate reducing power that is used by the mitochondrial respiratory chain to produce ATP through oxidative phosphorylation. The resultant increase in the cytosolic ATP/ADP ratio closes ATP-sensitive K + (K ATP ) channels, thus depolarizing the plasma membrane. Depolarization triggers opening of voltagegated Ca 2+ channels, and the influx of Ca 2+ ions consequently leads to exocytosis of insulin-containing granules from b-cells (2). This sequence of events illustrates that b-cell mitochondria exert strong control over GSIS (3), as mitochondrial energy-transducing processes dictate how fast and efficiently glucose is converted to ATP. Mitochondrial dysfunction impairs glucose-insulin secretion coupling and ultimately promotes b-cell apoptosis and death, one of the key features of type 2 diabetes (4).Mitochondria are dynamic organelles that are constantly remodeled through the opposing action of fission and fusion proteins (5). Until recently, the influence of mitochondrial dynamics over energy transduction has been underappreciated. The continuous changes in mitochondrial morphology are controlle...