Molecular Mechanisms Of Metabolic Control In The Arctic Ground Squirrel

Abstract

The annual cycle of the arctic ground squirrel (Spermophilus parryii) is characterized by periods of intense energy deposition and utilization, and therefore this species an attractive model for investigating the molecular mechanisms of metabolic control in mammals. In late summer, animals become hyperphagic and undergo intense fattening prior to hibernation. Leptin, a hormone produced by white adipose tissue, reverses obesity in rodent genetic models, but the effects of leptin on outbred rodent strains and wild species is modest. Similarly, administration of mouse recombinant leptin did not affect food intake or adiposity during prehibernation fattening in arctic ground squirrels. These results suggest that either prehibernation fattening is insensitive to negative feedback from leptin or that animals in general lack a negative feedback system controlling adiposity. At the terminus of prehibernation fattening, arctic ground squirrels commence hibernation, during which time nonshivering thermogenesis is invoked to maintain a high body temperature relative to sub-freezing ambient conditions. Thermogenesis occurs primarily by uncoupling oxidative phosphorylation and is catalyzed by mitochondrial membrane transport proteins. I compared the expression patterns of an established and a putative uncoupling protein gene (Ucp1 and Ucp3, respectively) in arctic ground squirrels as a function of temperature, hibernation, or fasting. As expected, levels of brown adipose tissue Ucp1 mRNA and protein were increased by cold exposure and hibernation and decreased by fasting. In contrast, levels of Ucp3 mRNA in skeletal muscle were not increased by cold or hibernation, but were paradoxically increased by fasting. Furthermore, I describe two independent studies that show that increases in the amount of UCP3 do not uncouple oxidative phosphorylation in vitro, suggesting that UCP3 does not mediate thermogenesis in skeletal muscle. Finally, I measured several parameters of mitochondrial bioenergetics in active and hibernating arctic ground squirrels to investigate if the reduced metabolic rate during hibernation is attributable to active suppression of metabolic rate or is instead a secondary consequence of the effects of low body temperature on enzyme kinetics. I show that mitochondrial substrate oxidation is depressed during hibernation, supporting the hypothesis that the reduced metabolic rate during hibernation is a partial consequence of active metabolic depression.