Skeletal Muscle Growth Hormone Receptor Signaling Regulates Basal, but Not Fasting-Induced, Lipid Oxidation Archana Vijayakumar1, YingJie Wu1,2, Nicholas J. Buffin1, Xiaosong Li3, Hui Sun1,2, Ronald E. Gordon 4 , Shoshana Yakar1,2, Derek LeRoith1* 1 Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, New York, United States of America, 2 David B. Kriser Dental Center, Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, 3 Departments of Medicine and Neuroscience, Albert Einstein College of Medicine, New York, New York, United States of America, 4 Department of Pathology, Mount Sinai School of Medicine, New York, New York, United States of America Abstract Background: Growth hormone (GH) stimulates whole-body lipid oxidation, but its regulation of muscle lipid oxidation is not clearly defined. Mice with a skeletal muscle-specific knockout of the GH receptor (mGHRKO model) are protected from high fat diet (HFD)–induced insulin resistance and display increased whole-body carbohydrate utilization. In this study we used the mGRHKO mice to investigate the role of muscle GHR signaling on lipid oxidation under regular chow (RC)- and HFD- fed conditions, and in response to fasting. Methodology/Principal Findings: Expression of lipid oxidation genes was analyzed by real-time PCR in the muscles of RC- and HFD- fed mice, and after 24 h fasting in the HFD-fed mice. Expression of lipid oxidation genes was lower in the muscles of the mGHRKO mice relative to the controls, irrespective of diet. However, in response to 24 h fasting, the HFD-fed mGHRKO mice displayed up-regulation of lipid oxidation genes similar to the fasted controls. When subjected to treadmill running challenge, the HFD-fed mGHRKO mice demonstrated increased whole-body lipid utilization. Additionally, under fasted conditions, the adipose tissue of the mGHRKO mice displayed increased lipolysis as compared to both the fed mGHRKO as well as the fasted control mice. Conclusions/Significance: Our data show that muscle GHR signaling regulates basal lipid oxidation, but not the induction of lipid oxidation in response to fasting. We further demonstrate that muscle GHR signaling is involved in muscle-adipose tissue cross-talk; however the mechanisms mediating this remain to be elucidated. Citation: Vijayakumar A, Wu Y, Buffin NJ, Li X, Sun H, et al. (2012) Skeletal Muscle Growth Hormone Receptor Signaling Regulates Basal, but Not Fasting-Induced, Lipid Oxidation. PLoS ONE 7(9): e44777. doi:10.1371/journal.pone.0044777 Editor: Raul M. Luque, University of Cordoba, Spain Received May 1, 2012; Accepted August 7, 2012; Published September 14, 2012 Copyright: 2012 Vijayakumar 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: X.L. is supported by the National Institutes of Health grant DK-20541. 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: derek.leroith@mssm.edu Introduction The metabolic outcomes associated with enhanced lipid oxidation in the skeletal muscle are contradictory. On the one hand, activation of lipid oxidation during and following exercise or fasting is associated with beneficial metabolic effects such as enhanced mitochondrial biogenesis and respiration, reduced inflammation, and improved glucose utilization. On the other hand, obesity and insulin resistance are also associated with increased lipid oxidation but result in impaired insulin action in the skeletal muscle (reviewed in [1]). The reason for this dichotomy was explained by Koves et al who demonstrated that insulin resistant muscles have lost their metabolic flexibility or the ability to switch between using carbohydrates and lipids in the fed and fasted states, respectively. They further reported increased fatty acid (FA) delivery and a higher rate of incomplete lipid oxidation in the muscles of obese, insulin resistant mice [2]. The ability of enhanced lipid utilization to hamper cellular glucose uptake and utilization has been described as the ‘‘glucose-fatty acid’’ cycle and may be involved in the above-mentioned effects [3,4]. Growth hormone (GH) is known to enhance whole-body lipid oxidation; however its regulation of substrate preference specifi- cally in the skeletal muscle is not clearly defined [5,6,7]. We have previously reported that mice with genetic loss of growth hormone receptors (GHR) specifically in the skeletal muscle (mGHRKO model) are protected from high-fat diet (HFD)-induced obesity and insulin resistance. Despite having a similar food intake, the mGHRKO mice had reduced fat mass, improved whole-body insulin sensitivity, and increased energy expenditure compared to the control mice when subjected to HFD feeding. Hyperinsulin- emic-euglycemic clamp studies revealed higher insulin-stimulated glucose uptake in the skeletal muscle and adipose tissue of the HFD-fed mGHRKO mice. Moreover, the respiratory exchange ratio (RER), which is an indicator of substrate preference, was also PLOS ONE | www.plosone.org 1 September 2012 | Volume 7 | Issue 9 | e44777