Date of Award

8-1-2017

Degree Name

Doctor of Philosophy

Department

Molecular Biology, Microbiology and Biochemistry

First Advisor

Nie, Daotai

Abstract

Ames dwarf mice have a spontaneous homozygous Prophet of Pituitary Factor 1 (Prop1) loss-of-function mutation. The Prop1 mutation results in a lack of differentiation of lactotrophs, thyrotrophs, and somatotrophs in the anterior pituitary. Without these endocrine cell types, Ames dwarf mice have essentially no circulating levels of growth hormone (GH), thyroid-stimulating hormone (TSH), and prolactin, and exhibit downstream hormonal deficiencies including insulin-like growth factor 1 (IGF-1), 3’,3,5-triiodothyronine (T3), and thyroxine (T4). Ames dwarf mice are exceptionally long-lived (40% to over 60% depending on sex and diet). They are also extremely insulin sensitive, have a delayed incidence of cancer, and have improved energy metabolism. While the extended lifespan and the many characteristics of an extended healthspan have been known for some time in Ames dwarf mice, the revelation that dwarf mice have improved energy metabolism was less than a decade ago. This finding came about at the molecular level (improved efficiency of the electron transport chain) and at the whole-animal level (increased oxygen consumption and decreased respiratory quotient). To date, however, few studies have been directed at furthering our understanding of the possible mechanism(s) by which Ames dwarf mice have altered energy metabolism. The goal of the studies presented in this dissertation is to delineate these mechanisms and to lay the groundwork for future studies that broaden our understanding of the role(s) of energy metabolism in the aging process. Project 1 examines the effects of early-life T4 replacement therapy in Ames dwarf mice. Previous work established that life-long T4 replacement therapy shortens lifespan in Snell dwarf mice (these mice have endocrine deficits that are essentially identical to those of Ames dwarf mice), while short-term replacement therapy during the early postnatal period of Ames dwarf mice does not. We hypothesized that T4 replacement therapy causes transient impairment of energy metabolism, which is why long-term T4 replacement therapy shortens longevity, and short-term replacement therapy does not. Supporting our hypothesis, we showed that short-term T4 replacement therapy during the early postnatal period transiently impaired energy metabolism as measured by indirect calorimetry. Following early-life T4 replacement therapy, we also observed an accelerated rate of sexual development, as well as lasting effects on bone physiology. Project 2 continued our investigation of energy metabolism by examining a highly metabolic tissue: brown adipose tissue (BAT), which is responsible for non-shivering thermogenesis. Our laboratory has already demonstrated functional alterations in visceral adipose tissue of Ames dwarf mice, and given the altered energy metabolism of Ames dwarf mice, we hypothesized that BAT may also be functionally unique compared to their normal littermates. Supporting our hypothesis, we observed alterations in gene expression, relative weight, and histological structure of BAT in Ames dwarf mice. Moreover, surgical removal of the interscapular BAT depot resulted in a unique physiological response, where Ames dwarf mice lost adiposity in their subcutaneous, perirenal, and epididymal white adipose tissue depots, thus contrasting with normal mice that gained adiposity. Project 3 built upon the findings of our second study, where we continued to examine the role of non-shivering thermogenesis and core body temperature in Ames dwarf mice. To further understand the role of non-shivering thermogenesis in glucose homeostasis and energy metabolism, we housed a cohort of Ames dwarf mice and their normal littermates at room temperature (23˚C), and another cohort at thermoneutrality (for mice this is 30˚C). We found that Ames dwarf mice placed at thermoneutrality had impaired glucose homeostasis and energy metabolism. This is an important finding because we and others believe both of these metabolic processes are important factors for longevity. Taken together, these studies indicate that the improved energy metabolism in Ames dwarf mice is dependent upon several factors, including a loss of thyroid hormone signaling and improved non-shivering thermogenesis.

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