Evaluation of peripheral repercussions resulting from chronic central treatment with irisin in C57BL/6 mice submitted to the model of Obesity and hypothalamic inflammation

• Grant number: 21/04794-8
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Effective date (Start): April 01, 2022
• Effective date (End): July 31, 2026
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Helena Cristina de Lima Barbosa
• Grantee: Tassiana Cristina Talpo
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Obesity results from an imbalance between energy intake and expenditure. It is often accompanied by insulin resistance, fasting hyperglycemia and several impairments in pancreatic beta cell function and survival, constituting one of the main risk factors for the development of Type 2 Diabetes Mellitus (T2D). Obesity is also associated with the development of hypothalamic inflammation, and this participates in the maintenance of Obesity through mechanisms that involve the reduction of central sensitivity to the anorexigenic hormones leptin and insulin, and the decompensation of autonomic impulses for important organs in the maintenance of energy homeostasis, such as pancreas and adipose tissues. Irisin, an adipomyocin released into circulation after physical exercise, is known for its participation in energy homeostasis through the browning of white inguinal adipose tissue. In vitro studies have pointed out its action in preserving beta cell functions in hyperglycemic conditions. In in vivo studies, peripheral treatment with irisin contributes to glucose homeostasis and beta cell function. The central treatment has been shown to be efficient in increasing energy metabolism, in addition to inducing an increase in the hypothalamic content of anorectic neuropeptides and decreasing the content of orexigenic neuropeptides. The aim of this study is to evaluate whether the intracerebroventricular (ICV) infusion of irisin, in mice submitted to the model of Obesity and hypothalamic inflammation, is able to improve pancreatic islet function and survival markers, as well as normalize the sympathetic and parasympathetic impulses for pancreas and white and brown adipose tissues, thus contributing to energy homeostasis. For this, C57BL/6 male mice will receive for 12 weeks a control diet (CTL; 10% lipids) or a high-fat diet (HFD; 45% lipids). 7 weeks after the start of the diets, a central leptin sensitivity test will be performed to confirm hypothalamic inflammation. Thereafter, the cannulation procedures and implantation of an osmotic micro pump will be performed, and then, treatments will begin. The animals will be treated with vehicle (0.9% saline; CTL and HFD groups) or irisin (87,5 ng/day; CTL-Iri and HFD-Iri groups) via ICV infusion (osmotic micro pump) for 7 consecutive days. Plasma irisin will be dosed on the last day of treatment. Glucose tolerance (via ipGTT), insulin sensitivity (via ipITT) and indirect calorimetry (via analysis of energy expenditure, respiratory quotient, metabolic flexibility and locomotor activity) will be investigated subsequently. In the 12th week, euthanasia will be performed. Blood samples will be used to obtain plasma, which will be analyzed: insulin, glucagon, leptin and pancreatic polypeptide. Hypothalamus will be removed and used to assess sensitivity to leptin. Pancreas will be used to obtain pancreatic islets, in which will be analyzed: (I) beta cell function markers; (II) exocytic function markers; (III) endoplasmic reticulum stress markers; (IV) markers of sympathetic activity; and (V) markers of parasympathetic activity. The white inguinal and brown adipose tissues will be removed and used to assess markers of sympathetic activity. This project will contribute to a better understanding of the peripheral benefits of chronic central treatment with irisin in an in vivo model of Obesity and hypothalamic inflammation. (AU)