Metabolic effect of stress: Sirt 1’s role in brain homeostatic and hedonic nuclei

INVESTIGATOR: Anika Toorie, Rhode Island College
THEME: Environmental Health Sciences
MENTOR: Elena Oancea, Brown University

ABSTRACT:  Adolescence is a critical period of development and stress incurred during this phase can affect immediate and long-term health. Glucocorticoids (GC), produced from activation of the hypothalamus-pituitary-adrenal (HPA) axis is critical in the resolution of stress. GC also regulate energy metabolism by affecting glucose homeostasis, feeding behaviors, and energy expenditure. Thus, stressful events may precipitate metabolic dysfunction depending on environmental conditions (1-5). Proposed studies will examine the metabolic effects incurred from prior adolescent stress exposure and adult diet condition to test the hypothesis that both acute and chronic mild stress experienced during mid-late adolescence activates the stress (HPA) axis, which then modulates the degree of response to an adult obesogenic dietary challenge. Moreover, we hypothesize that adolescent stress will yield diminished sensitivity of homeostatic and hedonic brain regions that regulate both reward/motivation and energy metabolism. Specifically, it is hypothesized that select dopamine and endorphin signaling networks in the adult brain is permanently reorganized due to prior adolescent stress-exposure, thereby increasing risk of metabolic
dysfunction. Dopamine and endorphins are neurotransmitters that help to impart feelings of pleasure and reward by acting on hedonic centers located in the midbrain, hypothalamus, basal ganglia (i.e., nucleus accumbens) and cortical nuclei (6-8). In Aim 1A, Sprague Dawley rats will be restraint stressed during early adolescence, mid-adolescence, or as young adults. Rats will then be fed a standard or obesogenic diet for 12-weeks and neurobehavioral and metabolic parameters assessed. Subsequently, for Aim 1B and 2A we will assess the metabolic effects of acute versus chronic stress during mid-late adolescence and adult dietary intake to test the hypothesis that persistent stress-induced enhancement of Sirt1 activity underlies aberrations to these homeostatic and hedonic pathways. Accordingly, rats will be exposed to an acute (single) or chronic (15- day repeat) restraint stress paradigm and then fed standard or obesogenic diets for 12-weeks. Neurobehavioral modifications will be investigated and transcriptome changes occurring in homeostatic and hedonic nuclei will be assessed as a potential mechanism underlying stress X diet- induced metabolic effects. Collectively, findings will enhance our knowledge of stress physiology, energy metabolism, and mechanisms governing the precipitation and progression of obesity and type 2-diabetes.

RELEVANCE: Obesity and type 2 diabetes are global public health issues arising from genetic and environmental risk factors. Persistent endocrine effects, stemming from early life stress exposures, can interact with adult diet condition thereby influencing metabolism and health. Elucidation of this interaction may identify novel, or further characterize existing, therapeutic targets in the treatment against diet induced obesity and diabetes.