Twelve-month-old male Sprague-Dawley rats exhibited a marked increase in percent adiposity and percent epididymal fat pad weight compared to their 2-month-old littermates. Aging was accompanied by deteriorated metabolic flexibility including decreased insulin sensitivity to glucose metabolism and increased hepatic lipid deposition. The alterations in adiposity and metabolic flexibility can be due to increased energy intake and/or decreased energy expenditure. Therefore, our first objective was to evaluate the status of energy intake and voluntary and involuntary energy expenditure in the animals. Our results show that food intake and voluntary energy expenditure as measured by locomotor activity were not responsible for the age-induced adiposity. Increased feed efficiency and decreased core body temperature in 12-month-old animals suggested that a reduction in resting metabolic rate (RMR) was responsible for their adiposity. Adaptive thermogenesis is an important component of RMR. We observed decreased mRNA levels of the major thermogenic gene, UCP1 in the brown adipose tissue (BAT) of 12-month-old animals that confirmed literature reports of decreased BAT mediated thermogenesis with age. Recently, subcutaneous white adipose tissue (sWAT) has also been shown to engage in thermogenesis though its contribution to energy expenditure and age mediated adiposity has not been investigated in detail. We hypothesized that decreases in inguinal WAT (IWAT) mediated thermogenesis contributes to the increased adiposity in 12-month-old animals. The next objective of our studies was to explore each step in the pathway of IWAT mediated thermogenesis including sympathetic nervous system (SNS) tone, SNS mediated lipolysis, fatty acid oxidation, mitochondrial biogenesis, and mitochondrial function in 2-month and 12-month-old male Sprague-Dawley rats. We observed decreases in β2-adrenergic receptor mRNA levels and adenylate cyclase activity in 12-month-old animals indicating that aging caused a decline in intracellular SNS tone in IWAT. Decreased SNS tone produced a decrease in the mRNA levels of its downstream target, the rate limiting lipolytic enzyme, hormone sensitive lipase but no change in the expression of the critical fatty acid oxidation gene, CPT1b. Twelve month old animals exhibited decreased mRNA levels of the master regulator of mitochondrial biogenesis, PGC1α, and decreased activity of citrate synthase, a marker of mitochondrial density. Accompanying these decreases in mitochondrial biogenesis was a decrease in mitochondrial function as evidenced by decreased mRNA levels of COX4i1, a marker of mitochondrial oxidative capacity and decreased activity of cytochrome c oxidase, a marker of complex IV activity in the electron transport chain. Finally, twelve month old animals exhibited decreased mitochondrial thermogenic capacity as evidenced by decreased mRNA and protein levels of UCP1. Twelve month animals also exhibited decrease in the complementary thyroid axis mediated thermogenesis evidenced in decreases in plasma levels of thyroxine (T4) and triiodothyronine (T3) and decreased IWAT mRNA and protein levels of Dio2 that will likely result in decreased tissue T3 levels. Overall, our findings indicate that in the IWAT, age is associated with decline in SNS mediated β-AR signaling for lipolysis that results in decreased fuel for thermogenesis. The decrease in fuel is exacerbated by a decreased mitochondrial capacity and function that compromises its ability to convert fuel to heat. Accompanying these reductions is a decrease in IWAT thyroid axis mediated thermogenesis. We conclude that age mediated decline in IWAT thermogenesis contributes to the marked increase in adiposity in male Sprague-Dawley rats.
|Advisor:||D'mello, Anil P.|
|Commitee:||Klase, Zachary A., Mercier, Isabelle, Holaska, Jim, Bentzley, Catherine|
|School:||University of the Sciences in Philadelphia|
|School Location:||United States -- Pennsylvania|
|Source:||DAI-B 81/5(E), Dissertation Abstracts International|
|Keywords:||Adiposity, Aging, Metabolic flexibility, Subcutaneous white adipose tissue, Thermogenesis|
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