Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice
Oksana Gavrilova, Bernice Marcus-Samuels, David Graham, Jason K. Kim, Gerald I. Shulman, Arthur L. Castle, Charles Vinson, Michael Eckhaus, Marc L. Reitman
Oksana Gavrilova, Bernice Marcus-Samuels, David Graham, Jason K. Kim, Gerald I. Shulman, Arthur L. Castle, Charles Vinson, Michael Eckhaus, Marc L. Reitman
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Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice

Abstract

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. 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. However, the improvement in triglyceride and FFA levels was modest. Donor fat taken from parametrial and subcutaneous sites was equally effective in reversing the phenotype. The beneficial effects of transplantation were dose dependent and required near-physiological amounts of transplanted fat. Transplantation of genetically modified fat into A-ZIP/F-1 mice is a new and powerful technique for studying adipose physiology and the metabolic and endocrine communication between adipose tissue and the rest of the body.

Authors

Oksana Gavrilova, Bernice Marcus-Samuels, David Graham, Jason K. Kim, Gerald I. Shulman, Arthur L. Castle, Charles Vinson, Michael Eckhaus, Marc L. Reitman

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Effect of fat transplantation on insulin sensitivity of A-ZIP/F-1 mice. ...
Effect of fat transplantation on insulin sensitivity of A-ZIP/F-1 mice. (a) Female mice (n = 3–9/group; transplanted with 900 mg of adipose tissue 5 weeks earlier) were fasted for 8 hours, then glucose (2 mg/g, intraperitoneally) was injected and blood glucose was measured at the indicated times. *P < 0.001 WT versus sham; +P < 0.02 transplanted versus sham. (b) Male mice (n = 3 to 9/group; transplanted with 900 mg of adipose tissue 8 weeks earlier) were fasted for 15–21 hours and then injected with insulin (0.75 mU/g), and blood glucose was measured at the indicated times. *P < 0.03 transplanted versus sham. (c) Tissue uptake of [14C]2-deoxyglucose in mice (n = 3/group, a subset of those in b) was measured 45 minutes after a single intraperitoneal injection. Muscle uptake was measured in gastrocnemius muscle and in either epididymal (WT) or transplanted adipose tissue. +P = 0.07, sham A-ZIP/F-1 versus wild-type; *P = 0.004, transplanted versus sham A-ZIP/F-1. dpm, disintegrations per minute. (d) Female mice (n = 4/group; transplanted with 900 mg of adipose tissue 6 weeks earlier) were fasted for 13 hours, then [3H]2-deoxyglucose (2-DG) uptake into extensor digitorum longus muscle in the absence (basal) or presence of insulin was measured. *P < 0.001 versus basal WT; **P = 0.01 versus insulin-treated WT; +P = 0.01 versus insulin-treated sham A-ZIP/F-1.