Thermoregulatory and heat-shock protein response deficits in cold-exposed diabetic mice.
Cold-induced expression of heat-shock proteins (HSPs) has been suggested to facilitate thermogenesis in brown adipose tissue (BAT). However, the regulation of this response and the mechanism supporting this facilitation have not been established. Because of the significant role of insulin in maintaining BAT thermogenesis, we employed a transgenic mouse model of diabetes to investigate the regulation and function of HSPs in BAT thermogenesis. These transgenic mice overexpress a calmodulin minigene regulated by the rat insulin II promotor, resulting in severe diabetes characterized by elevated blood glucose and glucagon that coincides with reduced serum and pancreatic insulin. Body temperature (Tb) of diabetic mice dropped significantly faster during a 3-h cold exposure (6 degrees C) than Tb of similarly treated control littermates. Cold exposure resulted in increased levels of constitutive and inducible HSP70 transcripts in control mice, but only constitutive HSP70 mRNA transcripts were induced in diabetic mice. Diabetes did not affect uncoupling protein induction, but cold-induced expression of members of other HSP families was reduced. Correspondingly, heat-shock regulatory factors were not activated in diabetic mice even though these factors were present. Phenylephrine induced HSP70 expression in control and diabetic animals, indicating that alpha-receptor-coupled HSP induction remained intact in BAT of diabetic mice. Insulin replacement restored the Tb response of diabetic mice as well as the HSP response. From these results it is clear that physiological signals that regulate cold-induced activation of BAT also regulate HSP expression in this tissue. This diabetic model provides a novel system in which the HSP response to cold has been selectively knocked out, making it a useful tool for the study of HSP regulation and function in BAT.
Matz
J M
JM
Department of Pharmacology and Toxicology, University of North Dakota, Grand Forks 58202, USA.
LaVoi
K P
KP
Epstein
P N
PN
Blake
M J
MJ
D002001:Adipose Tissue, Brown / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D001833:Body Temperature Regulation; D003080:Cold Temperature; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D006360:Heat-Shock Proteins / Q000096:biosynthesis / Q000172:deficiency*; D007328:Insulin / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D051381:Rats; D014158:Transcription, Genetic
D006360:Heat-Shock Proteins; D007328:Insulin