All ETDs from UAB

Advisory Committee Chair

Eric P Plaisance

Advisory Committee Members

Jose R Fernandez

Kevin R Fontaine

Tim R Nagy

Daniel L Smith, Jr

Document Type

Dissertation

Date of Award

2018

Degree Name by School

Doctor of Philosophy (PhD) School of Health Professions

Abstract

Ketogenic diet (KD) has been used to attenuate the decline in energy expenditure occurring from calorie restriction-induced weight loss, but long-term adherence can be difficult due to the strict nature of the diet. The growing body of evidence supporting KD-treatment of neurologic and metabolic diseases, as well as obesity, has prompted interest in the ability to increase circulating ketones via exogenous delivery. Ketone esters (KE) can raise blood ketone concentrations similarly to fasting and appear to reduce food intake acutely, but studies assessing effects on energy balance are limited and provide a potentially promising direction for weight control. Previous investigations using dietary KE differ in macronutrient composition, ester formula and concentration, and environmental conditions, possibly contributing to divergent results. Therefore, to expand our understanding of ketone metabolism, adipose biology, and the potential use of KE as a plausible treatment for obesity, the focus of this dissertation was to determine the effects of dietary R,S-1,3 butanediol diacetoacetate (BD-AcAc2) on components of energy balance while 1) feeding within a high-fat or high-carbohydrate diet, 2) testing different concentrations, and 3) manipulating environmental temperature to better model human metabolism, as potential effectors of BD-AcAc2. Dietary BD-AcAc2 at a minimum of 20% of calories resulted in reduced body weight (BW) and adiposity independent of diet macronutrient composition, housing temperature, and food intake. We observed an increase in energy expenditure attributed to increased markers of brown adipose tissue thermogenesis in obese mice consuming a high-fat diet + 30% BD-AcAc2, despite reduced food intake and BW compared to pair-fed controls. Moderately high-carbohydrate + BD-AcAc2 diets fed to lean mice did not result in increased metabolic rate, but still reduced BW and adiposity. Even animals with no reduction in feeding (20% and 25% BD-AcAc2 diets) weighed less, exhibited lower adiposity, and preservation of lean mass when compared to Control. Given the occurrence of weight loss without a decline in feeding or increase in energy expenditure, fecal energy loss was measured and appeared to contribute to the phenotype produced. In conclusion, dietary BD-AcAc2 affects multiple components of energy balance resulting in weight loss, but future mechanistic studies are needed.

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