Mechanism linking insulin resistance to defective thermogenesis in brown adipose tissue of obese diabetic SHR/N-cp rats.
We previously reported that the decreased sensitivity of brown adipose tissue (BAT) from obese Zucker rats to the calorigenic effects of norepinephrine is associated with a marked resistance to insulin, and we suggested that this defect may explain, at least in part, the increased energy gain efficiency of fa/fa rats. To test whether insulin resistance and/or diabetes leads to a reduced BAT thermogenesis in other genetic models of obesity, we compared BAT metabolic properties of obese Zucker rats with that of obese-nondiabetic LA/N-cp and obese-diabetic SHR/N-cp rats. It was found that the responsiveness and sensitivity of isolated brown adipocytes to the calorigenic effects of norepinephrine (10-100 mM) were markedly reduced in SHR/N-cp rats as compared to their lean controls (the Vmax was decreased by 3-4 times and the EC50 value was doubled). In the same cells, there was a similar decrease in the respiratory effects of dibutyryl cAMP (DBcAMP), revealing the presence of a major post-receptor defect. Remarkably, total cytochrome oxidase activity (an index of cell mitochondrial content) was also decreased by 3-4 times in SHR/N-cp rats, suggesting that a reduced BAT mitochondrial content is responsible for the defective thermogenesis. Similarly to Zucker rats, adipocytes isolated from SHR/N-cp rats were resistant to the metabolic effects of insulin (glucose transport and antithermogenesis). Cells from obese Zucker rats were also desensitized to the metabolic effects of norepinephrine and insulin but their thermogenic capacity was not reduced. In contrast, all the above parameters were normal in obese-nondiabetic LA/N-cp rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Marette
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A
Department of Physiology, Laval University Medical School, Québec, Canada.
Tulp
O L
OL
Bukowiecki
L J
LJ
D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001833:Body Temperature Regulation; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D003576:Electron Transport Complex IV / Q000032:analysis; D005260:Female; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D008928:Mitochondria / Q000201:enzymology; D009638:Norepinephrine / Q000494:pharmacology; D009765:Obesity / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D011918:Rats, Inbred SHR; D011924:Rats, Zucker
D007328:Insulin; D003576:Electron Transport Complex IV; D005947:Glucose; D009638:Norepinephrine