GIP-Overexpressing Mice Demonstrate Reduced Diet- Induced Obesity and Steatosis, and Improved Glucose Homeostasis Su-Jin Kim1, Cuilan Nian1, Subashini Karunakaran1, Susanne M. Clee1, Carlos M. Isales2, Christopher H. S. McIntosh1* 1 Department of Cellular & Physiological Sciences and the Diabetes Research Group, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada, 2 Departments of Orthopaedic Surgery and Cellular Biology and Anatomy, Georgia Health Sciences University, Augusta, Georgia, United States of America Abstract Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone that potentiates glucose-stimulated insulin secretion during a meal. Since GIP has also been shown to exert b-cell prosurvival and adipocyte lipogenic effects in rodents, both GIP receptor agonists and antagonists have been considered as potential therapeutics in type 2 diabetes (T2DM). In the present study, we tested the hypothesis that chronically elevating GIP levels in a transgenic (Tg) mouse model would increase adipose tissue expansion and exert beneficial effects on glucose homeostasis. In contrast, although GIP Tg mice demonstrated enhanced b-cell function, resulting in improved glucose tolerance and insulin sensitivity, they exhibited reduced diet-induced obesity. Adipose tissue macrophage infiltration and hepatic steatosis were both greatly reduced, and a number of genes involved in lipid metabolism/inflammatory signaling pathways were found to be down- regulated. Reduced adiposity in GIP Tg mice was associated with decreased energy intake, involving overexpression of hypothalamic GIP. Together, these studies suggest that, in the context of over-nutrition, transgenic GIP overexpression has the potential to improve hepatic and adipocyte function as well as glucose homeostasis. Citation: Kim S-J, Nian C, Karunakaran S, Clee SM, Isales CM, et al. (2012) GIP-Overexpressing Mice Demonstrate Reduced Diet-Induced Obesity and Steatosis, and Improved Glucose Homeostasis. PLoS ONE 7(7): e40156. doi:10.1371/journal.pone.0040156 Editor: Kathrin Maedler, University of Bremen, Germany Received April 12, 2012; Accepted June 1, 2012; Published July 3, 2012 Copyright: 2012 Kim et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: These studies were generously supported by funding to CHSM from the Canadian Diabetes Association (CDA) and the Canadian Institutes of Health Research (CIHR), and to SMC from the CDA. SMC holds a Canada Research Chair in the Genetics of Obesity and Diabetes and is a Michael Smith Foundation for Health Research (MSFHR) scholar. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: mcintoch@mail.ubc.ca Introduction Until recently, the major drugs utilized for treating type 2 diabetes (T2DM) were members of the sulfonylurea or meglitinide family, targeted at stimulating insulin secretion, biguanides (e.g. metformin) or thiazolidinediones, for reducing hepatic glucose output and insulin resistance, and a-glucosidase inhibitors for lowering carbohydrate digestion [1–2]. However, since sub- optimal glucose control or monotherapy failure often occur, combination therapy or, ultimately, insulin treatments are often needed [3–4]. Additional approaches have therefore been sought, including drugs based on the actions of the two incretin hormones, Glucose-dependent Insulinotropic Polypeptide (GIP) and Gluca- gon-like Peptide-1 (GLP-1), that convey insulinotropic signals from the gut to the pancreatic islets during a meal. Both GIP and GLP- 1 have been shown to exert a number of additional anti-diabetic actions, including promotion of b-cell survival and proliferation, and GLP-1 also inhibits glucagon secretion and reduces both gastric emptying and food intake [5–9]. Long-acting GLP-1 analogs (mimetics) and highly selective inhibitors of the incretin- degrading enzyme, dipeptidyl peptidase-4 (DPP-IV), are now widely used as T2DM therapeutics. The majority of studies on GIP to date have focused on its insulinotropic actions and b-cell functions, and long-term administration of DPP-IV resistant GIP analogues has been shown to markedly improve glucose tolerance in normal and diabetic rats, as well as in high fat (HF) fed mice [10–12]. Additionally, subcutaneous administration of D-Ala2-GIP1–30 to Zucker diabetic fatty rats resulted in potent anti-diabetic effects that included reduced b-cell apoptosis and improved b-cell function and glycemic control [13]. There is also strong evidence supporting a role for GIP in the regulation of fat metabolism that is consistent with its anabolic characteristics [9]. Among the adipocyte actions of GIP that have been identified are stimulation of adipogenesis, enhancement of lipoprotein lipase (LPL) activity, and increased lipolysis and fatty acid reesterifica- tion [14–21]. Studies showing that homozygous GIP receptor knockout (KO) mice (GIPRKO) were resistant to obesity when fed a HF diet [22] and the presence of K-cell hyperplasia and elevated GIP and insulin levels in HF fed rodents, led to the suggestion that GIP may contribute to the development of obesity, with associated insulin resistance and glucose intolerance [23–24]. Consequently, it has been proposed that GIP antagonist treatment [25], reducing circulating GIP levels with K-cell ablation [26] or vaccination against GIP [27] may be beneficial treatments for obesity. However, the question as to whether long- term elevation of GIP production causes detrimental pro-obesity effects has not been directly addressed and we have therefore PLoS ONE | www.plosone.org 1 July 2012 | Volume 7 | Issue 7 | e40156