THERMOREGULATORY AND HEAT-SHOCK PROTEIN RESPONSE DEFICITS IN COLD-EXPOSED DIABETIC MICE

Cold-induced expression of heat-shock proteins (HSPs) has been suggest ed to facilitate thermogenesis in brown adipose tissue (BAT). However, the regulation of this response and the mechanism supporting this fac ilitation have not been established. Because of the significant role o f insulin in maintaining BAT thermogenesis, we employed a transgenic m ouse model of diabetes to investigate the regulation and function of H SPs in BAT thermogenesis. These transgenic mice overexpress a calmodul in minigene regulated by the rat insulin II promotor, resulting in sev ere diabetes characterized by elevated blood glucose and glucagon that coincides with reduced serum and pancreatic insulin. Body temperature (T-b) Of diabetic mice dropped significantly faster during a 3-h cold exposure (6 degrees C) than T-b of similarly treated control litterma tes. Cold exposure resulted in increased levels of constitutive and in ducible HSP70 transcripts in control mice, but only constitutive HSP70 mRNA transcripts were induced in diabetic mice. Diabetes did not affe ct uncoupling protein induction, but cold-induced expression of member s of other HSP families was reduced. Correspondingly, heat-shock regul atory factors were not activated in diabetic mice even though these fa ctors were present. Phenylephrine induced HSP70 expression in control and diabetic animals, indicating that alpha-receptor-coupled HSP induc tion remained intact in BAT of diabetic mice. Insulin replacement rest ored the T-b response of diabetic mice as well as the HSP response. Fr om these results it is clear that physiological signals that regulate cold-induced activation of BAT also regulate HSP expression in this ti ssue. This diabetic model provides a novel system in which the HSP res ponse to cold has been selectively knocked out, making it a useful too l for the study of HSP regulation and function in BAT.