Conditional Deletion of ß-Catenin in the Mediobasal Hypothalamus Impairs Adaptive Energy Expenditure in Response to High-Fat Diet and Exacerbates Diet-Induced Obesity.

ß-Catenin is a bifunctional molecule that is an effector of the wingless-related integration site (Wnt) signaling to control gene expression and contributes to the regulation of cytoskeleton and neurotransmitter vesicle trafficking. In its former role, ß-catenin binds transcription factor 7-like 2 (TCF7L2), which shows strong genetic associations with the pathogenesis of obesity and type-2 diabetes. Here, we sought to determine whether ß-catenin plays a role in the neuroendocrine regulation of body weight and glucose homeostasis. Bilateral injections of adeno-associated virus type-2 (AAV2)-mCherry-Cre were placed into the arcuate nucleus of adult male and female ß-catenin flox mice, to specifically delete ß-catenin expression in the mediobasal hypothalamus (MBH-ß-cat KO). Metabolic parameters were then monitored under conditions of low-fat (LFD) and high-fat diet (HFD). On LFD, MBH-ß-cat KO mice showed minimal metabolic disturbances, but on HFD, despite having only a small difference in weekly caloric intake, the MBH-ß-cat KO mice were significantly heavier than the control mice in both sexes (p < 0.05). This deficit seemed to be due to a failure to show an adaptive increase in energy expenditure seen in controls, which served to offset the increased calories by HFD. Both male and female MBH-ß-cat KO mice were highly glucose intolerant when on HFD and displayed a significant reduction in both leptin and insulin sensitivity compared with controls. This study highlights a critical role for ß-catenin in the hypothalamic circuits regulating body weight and glucose homeostasis and reveals potential mechanisms by which genetic variation in this pathway could impact on development of metabolic disease.

Dietary wheat gluten induces astro- and microgliosis in the hypothalamus of male mice.

Gluten, which is found in cereals such as wheat, rye and barley, makes up a major dietary component in most western nations, and has been shown to promote body mass gain and peripheral inflammation in mice. In the current study, we investigated the impact of gluten on central inflammation that is typically associated with diet-induced obesity. While we found no effect of gluten when added to a low-fat diet (LFD), male mice fed high fat diet (HFD) enriched with gluten increased body mass and adiposity compared with mice fed HFD without gluten. We furthermore found that gluten, when added to the LFD, increases circulating C-reactive protein levels. Gluten regardless of whether it was added to LFD or HFD led to a profound increase in the number of microglia and astrocytes in the arcuate nucleus of the hypothalamus, as detected by immunohistochemistry for ionised calcium binding adaptor molecule 1 (Iba-1) and glial fibrillary acidic protein (GFAP), respectively. In mice fed LFD, gluten mimicked the immunogenic effects of HFD exposure and when added to HFD led to a further increase in the number of immunoreactive cells. Taken together, our results confirm a moderate obesogenic effect of gluten when fed to mice exposed to HFD and for the first-time report gluten-induced astro- and microgliosis suggesting the development of hypothalamic injury in rodents.

Leptin regulates glucose homeostasis via the canonical Wnt pathway in the zebrafish.

Leptin is best known for its role in adipostasis, but it also regulates blood glucose levels. The molecular mechanism by which leptin controls glucose homeostasis remains largely unknown. Here, we use a zebrafish model to show that Wnt signaling mediates the glucoregulatory effects of leptin. Under normal feeding conditions, leptin regulates glucose homeostasis but not adipostasis in zebrafish. In times of nutrient excess, however, we found that leptin also regulates body weight and size. Using a Wnt signaling reporter fish, we show that leptin activates the canonical Wnt pathway in vivo. Utilizing two paradigms for hyperglycemia, it is revealed that leptin regulates glucose homeostasis via the Wnt pathway, as pharmacological inhibition of this pathway impairs the glucoregulatory actions of leptin. Our results may shed new light on the evolution of the physiological function of leptin.

Central signalling cross-talk between insulin and leptin in glucose and energy homeostasis.

Energy homeostasis is controlled by an intricate regulatory system centred in the brain. The peripheral adiposity signals insulin and leptin play a crucial role in this system by informing the brain of the energy status of the body and mediating their catabolic effects through signal transduction in hypothalamic areas that control food intake, energy expenditure and glucose metabolism. Disruptions of insulin and leptin signalling can result in diabetes and obesity. The central signalling cross-talk between insulin and leptin is essential for maintenance of normal healthy energy homeostasis. An important role of leptin in glucoregulation has been revealed. Typically regarded as being controlled by insulin, the control of glucose homeostasis critically depends on functional leptin action. Leptin, on the other hand, is able to lower glucose levels in the absence of insulin, although insulin is necessary for long-term stabilisation of euglycaemia. Evidence from rodent models and human patients suggests that leptin improves insulin sensitivity in type 1 diabetes. The signalling cross-talk between insulin and leptin is likely conveyed by the WNT/ß-catenin pathway. Leptin activates WNT/ß-catenin signalling, leading to inhibition of glycogen synthase kinase-3ß, a key inhibitor of insulin action, thereby facilitating improved insulin signal transduction and sensitisation of insulin action. Interestingly, insights into the roles of insulin and leptin in insects and fish indicate that leptin may have initially evolved as a glucoregulatory hormone and that its anorexigenic and body weight regulatory function was acquired throughout evolution. Furthermore, the regulation of both central and peripheral control of energy homeostasis is tightly controlled by the circadian clock, allowing adaptation of homeostatic processes to environmental cues.