Growth hormone (GH) inhibits fat accumulation and promotes protein accretion, therefore the fall in GH observed with weight gain and normal aging may contribute to metabolic dysfunction. To directly test this hypothesis a novel mouse model of adult onset-isolated GH deficiency (AOiGHD) was generated by cross breeding rat GH promoter-driven Cre recombinase mice (Cre) with inducible diphtheria toxin receptor mice (iDTR) and treating adult Cre+/2,iDTR+/2 offspring with DT to selectively destroy the somatotrope population of the anterior pituitary gland, leading to a reduction in circulating GH and IGF-I levels. DT-treated Cre2/2,iDTR+/2 mice were used as GH-intact controls. AOiGHD improved whole body insulin sensitivity in both low-fat and high-fat fed mice. Consistent with improved insulin sensitivity, indirect calorimetry revealed AOiGHD mice preferentially utilized carbohydrates for energy metabolism, as compared to GH-intact controls. In high-fat, but not low-fat fed AOiGHD mice, fat mass increased, hepatic lipids decreased and glucose clearance and insulin output were impaired. These results suggest the age-related decline in GH helps to preserve systemic insulin sensitivity, and in the context of moderate caloric intake, prevents the deterioration in metabolic function. However, in the context of excess caloric intake, low GH leads to insulin output, and thereby could contribute to the development of diabetes. ; © Luque et al. This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The definitive version is available through Public Library of Science at DOI: 10.1371/journal.pone.0015767 ; This work was supported by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development Merit Award and NIH AG-031465 (to RDK); Grants from Programa Ramon y Cajal RYC-2007-00186, Programa Jose Castillejo JC2008-00220 and BFU2008-01136/BFI del Ministerio de Educacio´n y Ciencia e Innovacion (to RML) and Fondo de Investigacio´n sanitaria del ISCIII FI06/00804 (to JCC), Spain; NIH HL68585 and DK78165 (to PVS); Fund for Scientific Research (F.W.O.)-Flanders (Belgium) and the Research Fund of the K.U.Leuven (to HV).