Understanding How Obesity Increases Risk for Diabetes
Abstract
The FY21 PRMRP Topic Area: Diabetes. Rationale: Obesity and diabetes are common among Service Members as well as their dependents, with immense personal, societal, and financial costs. The rate of overweight and obesity has reached a staggering 70% in both active as well as retired Service Members. Obesity causes diabetes through insulin resistance, a condition in which muscles, fat, and liver exhibit an impaired response to insulin and cannot adequately take up glucose from blood to meet energy demands. However, the mechanisms through which obesity induces insulin resistance remain incompletely understood. While impairment of insulin signaling in the cell is commonly believed to account for insulin resistance, several studies indicate that in the early phase of obesity development, insulin signaling in the cell is still normal while insulin action, that is, the ability of insulin to lower blood glucose and fatty acids, is already markedly impaired. The sympathetic nervous system (SNS) is a pivotal mediator through which the brain controls the function of peripheral organs such as liver and fat that are important in metabolic regulation. Norepinephrine (NE) is the principal sympathetic neurotransmitter. Upon release from the sympathetic nerve terminals, NE diffuses to target tissues such as liver, fat, or muscle where it activates alpha1 adrenergic receptors causing increased cAMP signaling and consequent activation of multiple downstream molecular effectors that regulate metabolic processes within the cell. Preliminary data presented in this proposal suggest that insulin resistance in obesity may be chiefly induced through increased stress hormones such as NE and glucagon. Hence, in this proposal the role of the SNS in driving insulin resistance in obesity will be defined. Increased SNS activity has been described in patients with diabetes and obesity. However, whether increased SNS activity importantly contributes to the development of metabolic disease in obesity has not been well defined, largely due to the lack of suitable animal models to monitor sympathetic signaling in living animals. Hence, the two aims of this proposal are: (1) to test whether overnutrition-induced insulin resistance is due to increased SNS activity and stress hormones and (2) whether insulin resistance induced by obesity can be improved by reducing SNS and stress hormones. We have developed novel approaches to achieve these objectives and believe that the innovation provided within this proposal will have significant impact in the field. We expect that the outcomes of this study will change the way we understand and study insulin resistance and provide proof of concept for novel therapeutic strategies that prevent or ameliorate obesity-induced insulin resistance. Hypothesis: Increased SNS activity and stress hormones are key drivers of insulin resistance induced by obesity. Specific Aims: Aim 1: To test whether overnutrition-induced insulin resistance is due to increased stress hormones in the setting of unimpaired insulin signaling. (1a) We will test whether insulin signaling in the liver, fat, and muscle cells is altered during early, overnutrition-induced insulin resistance. (1b) To examine whether overnutrition increases the activity of the SNS and increases the release of the NE level in the synaptic cleft (the space between nerve terminal and target cell), we will implant cell-based neurotransmitter fluorescent engineered reporters (CNiFERs) into target tissue such as liver, fat, and muscle, and monitor NE level in real time in living animals. (1c) To test whether cAMP signaling in target cells is increased after short-term overnutrition by using cAMP Encoded Reporter (CAMPER) mouse. Aim 2: To identify strategies to improve obesity-induced insulin resistance. We will test whether a reduction of obesity induced sympathetic outflow and/or stress hormones is sufficient to reduce insulin resistance and metabolic dysfunctio
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210200
Entities
People
- Kenichi Sakamoto
Organizations
- Rutgers University
- United States Army