Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - HypoFlam (Targeting hypothalamic inflammation in obesity and diabetes)

Teaser

Incomplete understanding of the pathogenesis of the metabolic syndrome results in absence of efficient and safe medical therapies for the treatment of obesity, type 2 diabetes (T2D) and related metabolic diseases that are increasing worldwide at an alarming rate. Despite...

Summary

Incomplete understanding of the pathogenesis of the metabolic syndrome results in absence of efficient and safe medical therapies for the treatment of obesity, type 2 diabetes (T2D) and related metabolic diseases that are increasing worldwide at an alarming rate.
Despite considerable global economic, social and health efforts, the pandemic of obesity and T2D continues to expand, representing one of the most pressing and costly biomedical challenges confronting modern society. So far, neither public social and health interventions that require a drastic change in lifestyle (exercise and dieting), nor identifying better targets for more efficient obesity treatments, have had success in tackling this prevalence. Given the urgency for prevention and/or treatment, the scientific community has intensified efforts to better understand the mechanisms involved in the pathogenesis of obesity with the main goal to redefine/improve existing treatments to treat metabolic diseases.
Our research strategies focus on understanding of cellular, structural and functional changes occurring in hypothalamic nuclei responsible for metabolic control upon consumption of hypercaloric diets. As recently observed, obese-induced mice showed reactive microgliosis and astrocytosis which were associated with a decline in regulatory T-cells in the early stage of the metabolic syndrome. Based on these observations we hypothesized that hypothalamic inflammatory processes triggered by hypercaloric environments impair hormone sensing, disrupt glia and immune homeostasis that might incapacitate hypothalamus to control efficiently energy metabolism promoting the development of obesity and diabetes. Therefore, we propose: A) to develop a functional understanding of the pathophysiology of diet-induced hypothalamic inflammation, B) to test if hypothalamic inflammation plays a critical role in the development of the metabolic syndrome, and C) to target these novel pathogenic processes using novel targeted therapeutic approaches.

Work performed

So far, we have demonstrated that non-neural cells such as glia are able to directly influence the activity of hunger-sensing circuits for controlling brain feeding centres. Specifically, we uncovered that astrocytes, a specific type of glial cells, are key elements in relaying the accessibility of glucose from the periphery to the brain and ultimately determining the responsiveness of hypothalamic neurons in the control of feeding. Moreover, we recently found that astrocytes also regulate hypothalamic neovascularization previously observed in obese and diabetic mice. Besides astrocytes, we observed that combination of dietary fat and sugars, but not fat or obesity per se, is determinant for the induction of microglial activity and hypothalamic angiopathy, which are associated with the development of obesity. Our studies on immunosuppressive T cells revealed their functional role in glia crosstalk and local immune activation in the brain regions participating in regulation of systemic metabolism. Specifically, we discovered that Fox3+ Tregs depletion critically limits immune activation in hypothalamus under condition of hypercaloric challenge.
Finally, we tested hypothesis whether selective hypothalamic delivery of anti-inflammatory agents (specially-tailored GLP-1/dexamethasone conjugate) may reverse hypercaloric diet-induced hypothalamic inflammation. In a series of preclinical studies, the specially-tailored GLP-1/dexamethasone conjugate demonstrated GLP-1 receptor dependent glucocorticoid action in the brain and the ability to ameliorate obesity associated hypothalamic inflammation, to improve high-fat diet induced glucose intolerance and to decrease body weight. Furthermore, we discovered the therapeutic value of a novel combination of the “transient receptor potential cation channel subfamily M member 8” (TRPM8) agonist icilin with dimethylphenylpiperazinium (DMPP), a specific agonist at the nicotinic acetylcholine receptor subtype α3β4. This novel polypharmacotherapy approach showed significant improvement of body weight and glucose control in selected rodent models of obesity.

Final results

Our current findings support the hypothesis that hypothalamic glia and innate immune reactivity play a crucial role in hormone sensing and control of energy metabolism in the hypothalamus. In ongoing projects, we now continue to investigate mechanisms of non-neuronal regulation of the systemic metabolism to expand our knowledge on cellular and molecular targets for therapeutic interventions to tackle the metabolic syndrome. Further development of the non-neuronal-depending strategies to control sugar and lipid access to the brain will enable new breakthroughs in treatment of metabolic diseases associated with elevated glucose levels such as obesity and type-2 diabetes.