2nd International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 13-15 September 2000, Toronto, Canada

THE PHYSIOLOGY OF LIPOATROPHY

Antiviral Therapy 2000; 5(Suppl. 5):3 (abstract no. O1)

M Reitman
Diabetes Branch, NIDDK, NIH, Bethesda, Md., USA

First, I will review the physiology of brown adipose tissue, a tissue important for heat generation, particularly in small mammals. I will then discuss our work with a mouse model of lipoatrophic diabetes. In lipoatrophic diabetes, a lack of fat is associated with insulin resistance and hyperglycemia. This is in striking contrast to the usual association of diabetes with obesity. Transgenic mouse lines with reduced amounts of adipose tissue have been developed. In the A-ZIP/F-1 mouse, adipose tissue ablation was achieved by adipose-selective expression of a dominant negative protein that inactivates certain B-ZIP transcription factors. The A-ZIP/F-1 mice have virtually no white adipose tissue, a reduced amount of brown adipose tissue, leptin deficiency, severe insulin resistance and diabetes, and an accelerated adaptation to fasting. The A-ZIP/F-1 mice lack both adipose and non-adipose responses to a β₃-adrenergic agonist, CL316243. This suggests that even the non-adipose effects of β₃ agonists require adipose tissue. We have treated the A-ZIP/F-1 mice with leptin infusions. Leptin treatments at doses that achieve physiologic levels were only slightly effective; the mice remained hyper insulinemic and hyperglycemic. To understand the underlying mechanisms, we transplanted adipose tissue into A-ZIP/F-1 mice, which have a severe form of lipoatrophic diabetes. Transplantation of wild-type fat reversed the hyperglycemia, dramatically lowered insulin levels, and improved muscle insulin sensitivity, demonstrating that the diabetes in A-ZIP/F-1 mice is caused by the lack of adipose tissue. All aspects of the A-ZIP/F-1 phenotype, including hyperphagia, hepatic steatosis, and somatomegaly, were either partially or completely reversed. The beneficial effects of transplantation were dose-dependent and required near-physiological amounts of transplanted fat. These experiments demonstrate that the lack of fat is the cause of the metabolic abnormalities of lipoatrophy. We are continuing to dissect the contributions of adipose tissue that, when absent, cause diabetes.

000913
O1

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