Brain control of blood glucose levels

In many developed and mechanized countries, the readily access to highly palatable and caloric-dense food far exceeded the need for calories. This change has fostered the current pandemic of obesity and comorbid conditions of type 2 diabetes mellitus (T2DM), which are having negative impacts on public heath globally. Although it is evident that individuals develop central and peripheral insulin resistance upon exposure to an obesogenic environment, many questions are still unanswered. Owing to the sophisticated and technical nature of hyperinsulinemic-euglycemic clamp, laboratories around the world have adopted different procedural practices (eg. Restrained or anesthetized) to perform this canonical gold-standard technique. In particular, chapter 3 of this thesis has highlighted the impact of anesthesia and restrained stress on blood glucose levels in mice. By performing hyperinsulinemic-euglycemic clamp in conscious and free-moving mice, it allows careful analysis of systemic glucose homeostasis controlled by both the brain and peripheral organs in the most physiological setting possible. In addition, it provides important information that ultimately unveil new aspects of glucose regulation.
   Strong evidence in the literature have implicated central melanocortin pathways in the regulation of energy and glucose homeostasis. However, melanocortin pathways also exist in the periphery and the role of systemic melanocortins peptides is largely obscure. Essentially, chapter 4 of this thesis has identified a novel endocrine circuit of pituitary melanocortins, specifically -melanocyte stimulating hormone (-MSH) that regulates glucose uptake in skeletal muscle through the activation of a canonical melanocortin-5 receptor and protein kinase A (MC5r-PKA) pathway.
   Chapter 5 of this thesis explored the brain-centered glucoregulatory system in the context of obesity. Obesity is associated with reduced physiological responses to leptin and insulin, leading to the concept of obesity-associated hormonal resistance and elevated hepatic glucose production. The findings in chapter 5 have demonstrated that the reduction in insulin signaling in arcuate neurons of diet-induced obese mice is due to constitutive leptin activation of neurons, resulted from hyperleptinemia. Blocking leptin signaling in DIO mice consequently restores insulin signaling in the arcuate neurons. This effect is possibly mediated through the reduced inhibitory action of PTP1B on insulin receptor, thereby restoring the brain capacity to suppress hepatic glucose production in DIO mice.
   Noteworthy, obesity also causes ectopic lipid accumulation through hepatic de novo lipogenesis (DNL), which eventually leads to nonalcoholic fatty liver disease (NAFLD) and insulin resistance in peripheral tissues. Contradictory findings exist in the literature regarding the importance of carbohydrate response element-binding protein (ChREBP) expression in the liver and its association with insulin sensitivity. The findings in chapter 6 suggest that liver-specific ChREBP deletion results in hepatic insulin resistance in the absence or presence of excess lipid content in mice. Interestingly, blockade of transforming growth factor (TGF)-β/Smad3 signaling protects mice from obesity and diabetes. Given the functional diversity of Smad2 and Smad3, it is likely that common mediator smad (Co-Smad), Smad4, can function differently despite the fact that it participates in the same TGF-/Smad signaling pathway intracellularly. This necessitates the deletion of common mediator Smad, Smad4, to uncover the role of Smad4 in vivo. In chapter 7, a tamoxifen-inducible Smad4 conditional KO mouse model was generated in order to eliminate the possibility of embryonic compensation. Upon tamoxifen induction, Smad4 deletion enhances insulin sensitivity in lean mice by driving glucose uptake in brown adipose tissue (BAT). In addition, it also ameliorates insulin resistance in obese and insulin resistant mice, suggesting that Smad4 may be a potential target in the treatment of obesity and diabetes.
   Collectively, this thesis addresses the significance of both central and peripheral mechanisms in the regulation of glucose homeostasis. These findings have provided novel insights towards the understanding of systemic glucose regulation under normal and pathological conditions, which is vital for the development of therapeutic strategies to treat obesity and diabetes.