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United States Department of Agriculture

Agricultural Research Service

Research Project: MOLECULAR, CELLULAR, AND REGULATORY ASPECTS OF OBESITY DEVELOPMENT IN CHILDREN

Location: Children's Nutrition Research Center

Title: Ghrelin receptor null mice have reduced visceral fat and improved insulin sensitivity during aging

Authors
item Sun, Yuxiang -
item Saha, Pradip -
item Osifeso, Iyabo -
item Shao, Linda -
item Smith, Aga -
item Mcguinness, Owen -
item Chan, Larry -
item Smith, Roy -

Submitted to: Endocrine Journal
Publication Type: Abstract Only
Publication Acceptance Date: April 1, 2010
Publication Date: June 19, 2010
Citation: Sun, Y., Saha, P., Osifeso, I., Shao, L., Smith, A., Mcguinness, O.P., Chan, L., Smith, R.G. 2010. Ghrelin receptor null mice have reduced visceral fat and improved insulin sensitivity during aging [abstract]. Endocrine Journal. 31 (03): P2-512.

Technical Abstract: Aging is associated with a higher incidence of Type 2 diabetes; one in five Americans over age 65 has diabetes. Loss of lean mass and accumulation of fat, particularly visceral fat, during aging result in increased insulin resistance. Insulin resistance is a major pathogenic factor for Type 2 diabetes. Ghrelin is the only circulating orexigenic hormone known to increase growth hormone release, stimulate appetite and promote obesity. We have shown that ghrelin’s effects on GH release and appetite are mediated through GHS-R. More interestingly, we have found that ghrelin deletion increases glucose-induced insulin secretion and demonstrated that ghrelin deletion partially rescues the diabetic phenotype of leptin-deficient ob/ob mice. Acute ghrelin infusion has been shown to induce lipolysis and insulin resistance. Ghrelin receptor Ghsr-/- mice have reduced body weight, and body composition analysis suggests this may be primarily due to reduced abdominal fat. To determine whether deletion of the ghrelin receptor would improve age-associated insulin resistance, we performed insulin tolerance tests (ITT) on young, middle aged and old wild-type (WT) and Ghsr-/- mice to evaluate the effects of insulin on blood glucose. Young WT and Ghsr-null mice were both sensitive to insulin, and the difference between WT and Ghsr-null was not pronounced. As the mice aged, WT mice showed a marked increase in insulin resistance, whereas the Ghsr-null mice remained sensitive to insulin. Hyperinsulinemic-euglycemic clamps further demonstrated that the null mice have reduced glucose production, increased peripheral glucose infusion, and increased glucose uptake in skeletal muscle. In addition, we performed hyperglycemic and hypoglycemic clamps. Ghsr-/- mice secrete less insulin during hyperglycemic clamps, and require higher glucose infusion during hypoglycemic clamps. All functional studies support that Ghsr-/- mice have improved insulin sensitivity. In line with the functional data, old Ghsr-/- mice have significantly reduced epididymal fat (more than 50%) and reduced liver steatosis. Also, old Ghsr-/- mice have lower plasma cholesterol, triglyceride, free fatty acid and leptin. Consistently, the expression of adipocyte differentiation and lipid regulatory genes was reduced in the epididymal fat of old Ghsr-/- mice. Together, the data suggest that the reduced adipocyte differentiation in visceral fat may be, at least in part, the underlying mechanism that mediates the insulin-sensitive phenotype of Ghsr-/- mice. Hence, inactivation of GHS-R signaling reduces visceral fat and prevents age-associated insulin resistance, and GHS-R antagonists may have beneficial effects in preventing age-dependent onset of Type 2 diabetes.

Last Modified: 7/25/2014
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