Differential expression T4‐5’‐deiodinase activity in corpulent rats following cold exposure

Abstract

Multiple studies indicate that the thermic responses to diet and cold exposure may be impaired in obese rodents and are likely secondary to the combined contributions of sympathetic and thyroidal components of nonshivering thermogenesis (NST). T4 is normally deiodinated via outer ring deiodinase activity by D‐1 and/or D‐2 deiodinase activity to form hormonaly active T3 during fed and cold environments, or inner ring deiodinase activity via D‐3 to form reverse T3 (rT3) during food or energy deprivation. The effect of 14 hours of 4°C cold exposure on the obese phenotype of the LA/Ntul//‐cp rats was determined in normally reared young female animals 8 to 9 weeks of age and fed the Purina Chow #5012 ad libitum throughout. Body weights and adipose tissue mass were greater in the obese than the lean phenotype (p=<0.05). RMR and the dose related thermic responses to norepinephrine (NE, 200 ug., s.c.) were greater in lean than in obese. Cold exposure at 4°C resulted in decreases in rectal but not core temperature in obese rats, and the thermic responses to 45 minutes of 4°C cold exposure on VO2 were typical but were significantly greater in lean than obese animals at all time points measured. Circulating T4 concentrations were similar in lean and obese rats and serum T3 but not T4 concentrations increased dramatically in both phenotypes following the cold exposure, consistent with phenotype‐ and maximal IBAT‐linked changes in T4‐5’‐deiodinase activity / mg protein in kidney, liver and IBAT and in temperature linked increases in IBAT deiodinase activity / mg tissue protein in this strain. When D‐1 and D‐2 deiodinase activity was computed / tissue mass, further analysis indicated that D‐1 was the predominating deiodinase in liver, kidney, and gastrocnemius muscle, while in IBAT D‐2 > D‐1 activity / IBAT depot and was greater in obese than lean rats. Cold exposure was associated with modest increases in net kidney deiodinase activity only in kidney. Thus, the cold induced increases in circulating T3 in lean and obese rats are likely attributed at least in part to modest increases in renal T4‐5’ D‐2 deiodinase activity, in addition to maximal rates of conversion in other tissues in possible combination with decreases in hormone clearance rates during cold induced stress.

Nonshivering thermogenesis revisited: sympathetic and non-sympathetic contributions

“…22 In addition, measures of T4-5'deiodinase and T3 neogenesis were decreased in the obese phenotype, thereby implications for both endogenous tissues and nuclear factions to contribute to overall mechanisms of energy balance. [21][22][23][24] Both caffeine and the adrenergic activator ephedrine resulted in increases in nonshivering thermogenesis in man and animals, although likely via different biochemical mechanisms. 25 Ephedrine acts as an adrenergic agent, while caffeine and its primary metabolite, paraxanthine are selective inhibitors of cAMP phosphodiesterases, a broad class of cytoplasmic isoenzymes, thereby extending the actions of cAMP and cGMP on energy linked cellular activities including both calcium and potassium translocation in smooth muscle, where they can promote muscle relaxation.…”

“…14 Administration of the β-adrenergic agent norepinephrine can activate both glucose mobilization from glycogen stores and adrenergic activation of brown adipose tissue, and an increase in both glucose-mediated and BAT mediated thermogenesis.8,15,16 Peripheral sensitivity to the membrane associated actions of insulin are an essential element in glucose uptake in skeletal muscle and in both white and brown adipose tissue, and insulin resistance has been linked to impaired BAT thermogenesis on obese-diabetic rats. 15,16,17 BAT is heavily vascularized in addition to being broadly innervated by sympathetic neurons, and exogenous administration of adrenergic agents with stereospecific β3receptor affinity is similarly effective in activating biochemical pathways of BAT thermogenesis.6 Thus, the physiologic effects of noradrenaline administration resemble in part the responses elicited during cold induced activation of glucose mobilization and BAT thermogenic activity and are independent of shivering induced components of thermogenesis occurring in the skeletal muscle of mammalian organisms in direct response to early cold acclimatation. Danforth et al 8,17 have reported that infusion of glucose can increase energy expenditure independent of adrenergic stimulation during the quietly resting state.…”

“…4 Administration of noradrenaline readily stimulates BAT tissues, resulting in marked increases in VO2, a measure of thermogenesis, with corresponding increases in plasma glucose mobilization from glycogen, and in cellular glucose uptake of BAT and peripheral tissues. [5][6][7][8][15][16][17] The above responses are impaired in the obese phenotypes of the obese rat strains at least in part secondary to insulin resistance in peripheral tissues, in addition to additional hormonal dysregularities that may contribute to the impaired thermogenic responses and further contribute to impaired glucose uptake and metabolism. 4,18 Measures of protein turnover represent the most energetically expensive processes of peripheral tissues, at 4 high energy phosphate bonds per peptide bond forms, and have also been shown to be diminished by 50% or more in the obese phenotype, thereby further contributing to the expression of the obese state.…”

Treatment with α-Methylparatyrosine Inhibits Sympathetic but Not Thyroidal Responses to Diet-Induced Thermogenesis in Lean Cafeteria-Overfed Rats

“…Thus, the use of α-MPT is well suited for the qualitative separation of the SNS and thyroidal components 0f DIT and NST, especially since it has long to been known to be without any effects on iodothyronine metabolism in rats or humans, in contrast to insulin and nutritional factors, both of which are linked to iodothyronine deiodination. [16][17][18][19] Thus, the purpose of the present study was to determine the relative contributions of the SNS and non-SNS components of NST in lean rats fed a low glycemic chow diet or chronically overfed with a Café diet feeding regimen.…”

“…The lean phenotype of the congenic LA/Ntul//-cp rat strain typically remains quite lean throughout its life span, and its thermogenic responses to alterations in diet and environmental stimuli including the effects on specific isoforms of the deiodinase enzymes have been demonstrated to respond favorably and in a predictable manner. 2,20,21…”