Impact of High Fat Diet and Ethanol on Metabolic and Neuroimmune Function
Open Access
- Author:
- Coker, Caitlin
- Graduate Program:
- Anatomy
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- July 13, 2020
- Committee Members:
- Yuval Silberman, Dissertation Advisor/Co-Advisor
Yuval Silberman, Committee Chair/Co-Chair
Patricia Mclaughlin, Committee Member
Andras Hajnal, Committee Member
Helen Marie Kamens, Outside Member
Patricia Sue Grigson Kennedy, Committee Chair/Co-Chair
Nicholas Michael Graziane, Committee Member
Patricia Mclaughlin, Program Head/Chair - Keywords:
- High Fat Diet
Ethanol
Obesity
Alcohol Use Disorder
Neuroimmune
Insulin
Glucose - Abstract:
- Obesity and alcoholism are two of the most prevalent chronic conditions in the United States and make up the second and third leading causes of preventable deaths nationwide. Chronic intake of obesogenic diets high in fat (high fat diet, HFD) and alcohol (EtOH) cause similar, and potentially interactive, behavioral and metabolic symptoms, resulting in an increased risk for developing subsequent disease states. This interaction may be caused by diet- and EtOH-mediated changes in brain regions controlling hedonic intake and insulin/glucose homeostasis. Part 1 of this dissertation examines if HFD versus a control chow diet alters voluntary two-bottle choice EtOH intake in mice given differing access schedules and assesses the resultant impact on metabolic function via insulin and glucose tolerance tests. Overall, mice given unlimited access to both EtOH and HFD consumed significantly less EtOH and were insulin resistant and hyperglycemic compared to unlimited access to EtOH and chow diet. EtOH consumption given in limited access periods did not differ between mice given HFD and chow diet, but HFD-fed mice exhibited hyperglycemia, insulin resistance, and glucose intolerance. Mice given HFD in a single 24-hour session per week and limited access to EtOH the remainder of the week displayed binge-like eating behaviors and consumed significantly more EtOH than mice given ad libitum chow or HFD. These mice did not have significantly altered body composition, but developed insulin resistance and glucose intolerance. It is well known that obesity is associated with insulin resistance. While the precise link has yet to be fully determined, evidence suggests one potential mechanism linking the two is inflammation. Part 2 of this dissertation determines if inhibiting inflammation with minocycline reduces adverse metabolic consequences associated with HFD-induced obesity in mice and if any metabolic improvements are associated with reduced hypothalamic microglia activity, a brain region involved in controlling metabolic functions such as food intake, energy expenditure, and glucose homeostasis. As a result, minocycline treatment was associated with a decrease in HFD-induced weight gain, an improvement in insulin sensitivity, and a decrease in active microglia in the paraventricular nucleus of the hypothalamus. These effects occurred independent of changes in food or water intake as well as changes in HFD-induced peripheral inflammation. Overconsumption of HFD prior to adulthood, along with other co-morbid factors such as a sedentary lifestyle, has promoted an epidemic in children and adolescents with overweight and obesity, which may result in long-lasting changes in mechanisms regulating adult physiology. These changes may be further influenced by adult EtOH intake leading to increased risk of metabolic disorders. One potential mechanism linking early-life HFD over-nutrition and adult EtOH intake with an increased risk of adult metabolic disorders may be related to the known effects of both HFD and EtOH on peripheral and central immune signaling. Part 3 of this dissertation establishes a model to assess adolescent HFD and early adult EtOH exposure interactions on whole-body insulin and glucose homeostasis in mice and determines if decreasing immune activity during the adolescent HFD period regulates this interaction. Findings of this study indicate early-life HFD consumption affects EtOH-induced metabolic responses during adulthood and reducing immune activation during the adolescent HFD period with minocycline treatment attenuates these metabolic disruptions. In summary, this dissertation shows how access schedules mediate the impact of HFD on EtOH intake and insulin/glucose function. When exploring the potential mechanism between obesity and its negative metabolic consequences, we suggest that hypothalamic microglia activation is associated with HFD-induced obesity and metabolic dysfunction. Additionally, our study determining the interactions of adolescent over-nutrition with HFD and adult EtOH exposure on metabolic and immune function suggests inflammatory responses cultivated during adolescent HFD exposure have long-lasting affects which alter the modulation of insulin function and glucose homeostasis in adulthood following EtOH exposure.