Growth hormone (GH) is produced by somatotropes of the anterior pituitary gland and is released into the general circulation where it stimulates the production of insulin-like growth factor I (IGF-I) from multiple target tissues. GH and IGF-I work in concert to mediate various aspect of cellular function. In normal individuals, circulating GH/IGF-I levels steadily rise after to birth, plateau around the peripubertal period, then decline thereafter at a rate of ~14% for every decade of life. Circulating GH levels also decline with weight gain, independent of age. Based on human and animal studies examining the metabolic impact of GH deficiency (GHD), with and without GH or IGF-I replacement, it is clear that GH can inhibit fat accumulation and promote protein accretion, while the metabolic actions of IGF-I resemble those of insulin. GH and IGF-I are also reported to have positive effects on pancreatic b-cell function, cardiovascular performance and bone remodeling. The metabolic benefits of GH replacement in GHD patients has fueled the off-label use and abuse of GH in normal healthy adults to enhance body image and athletic performance, as well as providing a rationale for GH replacement in elderly and/or obese individuals to help combat metabolic disease. Despite the potential positive effects of GH in adults, there is also ongoing debate whether GH, at physiologic levels, can reduce insulin sensitivity, exacerbate cancer, and shorten lifespan. The true importance of endogenous GH in maintaining health OR promoting disease in adults, remains to be clarified since the bulk of our knowledge is based on studies of 1 ) acute or long-term GH administration in normal subjects, 1) developmental GHD, that might not reflect the consequences of GH decline after sexual maturation and 2) adult onset GHD (AOGHD) which is frequently accompanied by other pituitary defects, making it difficult to determine what changes are due specifically to GH loss. In addition, in humans it is difficult to separate out the confounding effects of genetics, environment and lifestyle from those due specifically to endocrine pathologies. To circumvent these problems and more accurately define the importance of endogenous GH in adult (patho)physiology the current proposal will utilize a unique genetically engineered mouse model of adult-onset, isolated GHD (AOiGHD). Preliminary studies demonstrated when AOiGHD mice were fed a low-fat diet, adipose mass increased, but whole body insulin sensitivity improved. However, diet-induced obese AOiGHD mice developed glucose intolerance which was associated with low fed and fasted insulin levels, suggesting GH/IGF-I may also be important in maintaining b-cell function. Given multiple organs systems are involved in maintaining glucose homeostasis, the proposed series of studies will take an integrative approach to determine 1) at what level AOiGHD impacts b-cell function (insulin expression, proliferation, neogenesis and/or apoptosis), 2) if the AOiGHD-induced increase in insulin sensitivity is due to global improvement in insulin actions or due to tissue-specific changes (liver, fat, skeletal muscle) 3) determine if AOiGHD will influence whole body metabolism and weight changes in response to acute fasting/refeeding or longterm diet-induced weight loss. Knowledge gained from these studies will provide important information regarding the benefits or risks of GH replacement therapy.
Project Narrative Relevant to our modern society is determining if the normal fall in growth hormone (GH) that occurs with weight gain and age, is a major contributor to the deterioration of metabolic function. This proposal will utilize a novel mouse model of adult-onset, isolated GH deficiency (AOiGHD) to identify the key components of the metabolic homeostatic system that are most profoundly affected by selective reduction in circulating GH and IGF-I, in the context of sex, diet and nutrient availability. Information gained can be used in future experiments to determine if GH acts directly or indirectly on specific tissues/cells to mediate these effects.
|Kineman, Rhonda D; Majumdar, Neena; Subbaiah, Papasani V et al. (2016) Hepatic PPARÎ³ Is Not Essential for the Rapid Development of Steatosis After Loss of Hepatic GH Signaling, in Adult Male Mice. Endocrinology 157:1728-35|
|Cordoba-Chacon, Jose; Majumdar, Neena; Pokala, Naveen K et al. (2015) Islet insulin content and release are increased in male mice with elevated endogenous GH and IGF-I, without evidence of systemic insulin resistance or alterations in Î²-cell mass. Growth Horm IGF Res 25:189-95|
|Luque, RaÃºl M; IbÃ¡Ã±ez-Costa, Alejandro; Neto, Leonardo Vieira et al. (2015) Truncated somatostatin receptor variant sst5TMD4 confers aggressive features (proliferation, invasion and reduced octreotide response) to somatotropinomas. Cancer Lett 359:299-306|
|Cordoba-Chacon, Jose; Majumdar, Neena; List, Edward O et al. (2015) Growth Hormone Inhibits Hepatic De Novo Lipogenesis in Adult Mice. Diabetes 64:3093-103|
|IbÃ¡Ã±ez-Costa, Alejandro; CÃ³rdoba-ChacÃ³n, JosÃ©; Gahete, Manuel D et al. (2015) Melatonin regulates somatotrope and lactotrope function through common and distinct signaling pathways in cultured primary pituitary cells from female primates. Endocrinology 156:1100-10|
|Gahete, Manuel D; CÃ³rdoba-ChacÃ³n, JosÃ©; Lantvit, Daniel D et al. (2014) Elevated GH/IGF-I promotes mammary tumors in high-fat, but not low-fat, fed mice. Carcinogenesis 35:2467-73|
|Cordoba-Chacon, Jose; Gahete, Manuel D; McGuinness, Owen P et al. (2014) Differential impact of selective GH deficiency and endogenous GH excess on insulin-mediated actions in muscle and liver of male mice. Am J Physiol Endocrinol Metab 307:E928-34|
|Cordoba-Chacon, Jose; Gahete, Manuel D; Pokala, Naveen K et al. (2014) Long- but not short-term adult-onset, isolated GH deficiency in male mice leads to deterioration of Î²-cell function, which cannot be accounted for by changes in Î²-cell mass. Endocrinology 155:726-35|
|Luque, RaÃºl M; CÃ³rdoba-ChacÃ³n, JosÃ©; IbÃ¡Ã±ez-Costa, Alejandro et al. (2014) Obestatin plays an opposite role in the regulation of pituitary somatotrope and corticotrope function in female primates and male/female mice. Endocrinology 155:1407-17|
|CÃ³rdoba-ChacÃ³n, Jose; Gahete, Manuel D; Pozo-Salas, Ana I et al. (2013) Endogenous somatostatin is critical in regulating the acute effects of L-arginine on growth hormone and insulin release in mice. Endocrinology 154:2393-8|
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