SPECIFIC DECREASE OF MITOCHONDRIAL THERMOGENIC CAPACITY IN BROWN ADIPOSE-TISSUE OF OBESE SHR N-CP RATS/

The metabolic properties of brown adipose tissue (BAT), liver, and ske letal muscles were compared in lean and obese diabetic SHR/N-cp rats ( a new model of type II diabetes) to test whether the severe insulin re sistance of obese animals is specifically associated with a thermogeni c defect in BAT. The respiratory response of brown adipocytes to norep inephrine and to agents bypassing the adenylate cyclase complex (dibut yryl cyclic AMP and palmitate) was decreased by two-thirds in obese ra ts, thereby indicating the presence of a major postreceptor defect. Si gnificantly, total BAT cytochrome oxidase activity, uncoupling protein content, and mitochondrial guanosine 5'-diphosphate binding (3 indexe s of BAT thermogenic capacity) were also decreased by two-thirds. The specific activities of these parameters expressed per total BAT mitoch ondrial protein were not altered either. This indicates that the total number of mitochondria per cell is decreased in BAT of obese rats. In contrast, total tissue cytochrome oxidase activity, protein content, and DNA content all increased by two to three times in the liver of ob ese SHR/N-cp rats, but these parameters remained unchanged in skeletal muscles (vastus lateralis and soleus). Such a remarkable liver hypert rophy may have occurred as a consequence of the persistent hyperphagia -hyperinsulinemia of obese rats that induced a hyperplasia and/or a he patocyte polyploidization. This observation together with the fact tha t daily energy expenditure associated with food intake was markedly in creased in obese rats (representing as much as 25% of the total energy expenditure) strongly suggests that the liver plays a major role in e nergy balance in these animals. It is concluded that there is a specif ic regression of mitochondria in BAT, but not in other important oxida tive tissues (liver and skeletal muscles), of obese SHR/N-cp rats. Wit h the consideration that insulin deficiency in streptozotocin-induced diabetic rats (a model of type I diabetes) similarly decreases total B AT cytochrome oxidase activity and uncoupling protein content, it is s uggested by analogy that severe insulin resistance (associated with di abetes) in obese spontaneously hypertensive rats represents a major fa ctor leading to mitochondrial regression in BAT.