Role of IL-9 signaling in the pathogenesis of obesity and aging and in helminth-mediated immunomodulation in type 2 diabetes

• Applicant: Indulekha Karunakaran, Ph.D.
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 515635851

An unprecedented increase in the incidence of obesity and type 2 diabetes has caused a twin epidemic of obesity and type-2 diabetes termed ‘diabesity’. Thanks to a growing body of research, the simplistic view of these conditions as just energy imbalance disorders is long expired and they are now acknowledged as inflammatory disorders. This shift in view has brought the adipose tissue to the forefront of diabetes-obesity research and how its repertoire of myriad inflammatory as well as anti-inflammatory mediators act to achieve metabolic homeostasis is being actively investigated. To this end, the major aim of the project is to investigate the interleukin family member IL-9 in obesity-induced and aging-induced insulin resistance and its role in imparting helminth-mediated protection against type 2 diabetes. Despite other type 2 cytokines showing insulin sensitizing effects during diet-induced insulin resistance, the role of IL-9 has not yet been studied so far. Preliminary data in IL-9 receptor knock out (IL-9R KO) mice showed reduced glucose and insulin tolerance and increased inflammation and pharmacological treatment of recombinant IL-9 during high fat feeding in wild type mice improved insulin resistance and inflammation. This data suggests that IL-9 mitigates insulin resistance and inflammation during obesity. On the other hand, during age-induced insulin resistance, a reversal of role of IL-9 was observed with aged IL-9R KO mice showing a better glucose tolerance, in line with other reports demonstrating a differential effect of eosinophils and regulatory T cells during aging. To investigate the differential effects of IL-9 in obesity and aging-induced insulin resistance, the following research questions will be addressed • How does IL-9 signaling confer insulin sensitivity and counteract inflammation during obesity-associated insulin resistance? • How does IL-9 orchestrate its reversal role during age-associated insulin resistance? To address these aims mechanistic studies will be conducted in IL-9R KO mice with special focus on the NLRP3 inflammasome and adiponectin signaling will be investigated in the adipose tissue and liver. The effects of IL-9 on the hallmarks of ageing like physical fitness, immunological fitness, bone marrow hematopoiesis will be investigated in the aged IL-9R KO mice. Based on the type-2 dependent helminth-mediated protection observed during diet-induced insulin resistance and the central role of IL-9 in driving host protective immunity against helminths, the question of whether helminths might act via IL-9 to induce insulin sensitivity during diet-induced insulin resistance will be addressed. Further, helminth-induced immunometabolic changes that lead to the insulin sensitiizing effects during obesity will be investigated. In addition, we will confirm our results in human samples obtained from an ongoing study in Cameroon on the association between diabetes and helminth infections.

• DFG Programme: Research Grants