This is an application for a VA Career Development Award II that will provide protected time and resources for the applicant to bridge to independence. Under the mentorship of leaders acclaimed in their fields, she will be able to mature into an independent clinical investigator. In order to achieve this, her primary career development objectives under this award include: 1) establish expertise in in vivo insulin and glucose metabolism measurements 2) develop skills in functional MRI (fMRI) neuroimaging and analyses 3) enhance understanding of obesity related neuroscience, 4) develop expertise in conducting weight loss intervention trials, 5) collect preliminary data for a VA merit award application, 6) continue to develop cross-disciplinary collaborations, and 7) continue training in responsible conduct of research. The current research proposal will explore the hypothesis that insulin resistance contributes to decreased food consumption reward signaling, thereby increasing vulnerability to overeat and impairing weight loss. In most obese individuals, insulin signaling is impaired (insulin resistance). Preclinical animal studies suggest that insulin resistance in brain regions important for reward contribute to overeating. This proposal aims to test these hypotheses in humans and to determine if these characteristics are pertinent to clinical outcomes (food intake and weight loss). In humans increased body mass index (BMI) and weight gain occur with decreased food consumption-induced neural activation (consummatory reward) in the caudate of the dorsal striatum. It has been speculated that diminished consummatory reward causes overeating and prevents weight loss; however, this hypothesis has not been directly tested. Further, mechanisms for impaired food consumption-induced neural activation in obesity have not been investigated. The primary research outcomes of the proposed study are: 1) insulin sensitivity determined by the gold standard hyperinsulinemic euglycemic clamp, 2) food consumption-induced neural activation in the caudate as determined by blood-oxygen dependent functional magnetic resonance imaging (BOLD fMRI) scanning, 3) caloric intake at a buffet meal, and 4) weight loss during a weight loss intervention and 6 months after completing the intervention. We will enroll 55 obese Veterans, 40 who are insulin resistant and 15 who are insulin sensitive. The groups will be stratified by gender and be similar in age and BMI. All will complete baseline assessment of outcomes. After this, the insulin resistant obese will be randomized to: 1) lose 5-10% of total body weight (TBW) over 4-6 months or 2) maintain current body weight for 4-6months before completing the post assessment of outcomes. Participants will return 6 months after completion of their respective intervention for a weight measurement. This approach will permit us to explore 3 aims: 1) determine whether weight loss-induced improvements in insulin sensitivity occur with improved (increased) food consumption-induced neural activation and whether neural activation predicts long term (6 month) weight loss, 2) determine whether insulin sensitive obese have greater neural activation to food consumption compared to insulin resistant obese, and 3) determine if food consumption-induced neural activation predicts food intake at a buffet meal. Secondary measures of the study include whole brain activation analyses, neuroendocrine hormone measurement at the time of imaging, psychometric measures including eating behaviors and personality characteristics, and measures of reward sensitivity. A comprehensive career development plan is provided, designed to prepare the applicant for independence through mentorship and training activities. This award provides the applicant the time and resources to build a career as an independent VA clinical investigator focusing on the neuroendocrine mechanisms that perpetuate human obesity.
Obesity is a common problem in the veteran population as at least 1 in 3 Veterans are obese. Obesity causes poor health outcomes such as type 2 diabetes, heart attacks, and early death. Most people who try to lose weight are unable to do so. When obese people eat food they have less response in areas of the brain that sense pleasure (reward) as compared to non-obese people. Decreased pleasure response to food predicts future weight gain. It is not known if this poor brain response is reversible or why obese people's brains respond this way. Insulin in the brain regulates the brain's pleasure sense. As people gain weight, the function of insulin becomes impaired. We will study if impaired function of insulin is related to a poor brain response to food and if this brain response predicts food intake and change in weight. We will, also, study if improving the function of insulin with weight loss improves the brain response. These studies will improve the understanding as to why weight loss is difficult and if improving insulin signaling is a potential way to treat obesity.
