Inappropriate accumulation of fat in the liver leads to hepatic insulin resistance and inflammation which can progress to liver fibrosis. Therefore, understanding the mechanisms regulating hepatic lipid metabolism is critical in optimizing the diagnosis and treatment of metabolic diseases that are common in the Veteran population including obesity, diabetes mellitus and hyperlipidemia. In that the liver is a major target of growth hormone (GH), coupled with the fact that developmental- and disease-associated changes in GH secretion/action are associated with alterations in hepatic lipid accumulation, understanding how GH regulates hepatic lipid metabolism is clinically relevant. A clear picture of the direct effectsof GH on hepatic lipid processing is clouded by the fact that GH also alters whole body insulin sensitivity, insulin production and substrate availability (glucose and free fatty acids), all of wich are confirmed modulators of hepatic lipid metabolism. Separating out the relative roles of GH and insulin is further complicated by the fact that insulin, as well as GH, supports hepatic GH signaling and insulin-like growth factor I (IGF-I) production, and IGF-I and insulin serve as negative feedback regulators of GH secretion. Given the complex interrelationship between GH and insulin, experimental alteration in the output or signaling of one will inevitably lead to changes in the other. In order to circumvent these problems, the proposed series of experiments will take advantage of unique genetically engineered mouse models, developed by our laboratory, that clamp GH and insulin input to the liver. In this proposal, we will use genetically engineered animal models to achieve 1) controlled elevation of both GH and insulin, 2) high/normal GH in the absence of hepatic insulin signaling and 3) high/normal insulin in the absence of hepatic GH signaling. These in vivo models will be used in conjunction with primary hepatocyte cultures to address the following SPECIFIC AIMS: A) Determine if GH modifies insulin-mediated changes in hepatic lipid metabolism, B) Test if insulin is essential for GH-mediated regulation of hepatic lipid metabolism, and C) Examine the impact of adult-onset hepatic GH resistance on lipid metabolism. The knowledge gained will aid in the better understanding of the development, progression, diagnosis and treatment of metabolic diseases.

Public Health Relevance

This series of in vivo and in vitro studies are designed to unravel the complex interrelationship between GH and insulin on hepatic lipid metabolism, where the knowledge gained will aid in the better understanding of the development, progression, diagnosis and treatment of metabolic diseases that are common in the Veteran population.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Endocriniology A (ENDA)
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Jesse Brown VA Medical Center
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Cordoba-Chacon, Jose; Sarmento-Cabral, Andre; Del Rio-Moreno, Mercedes et al. (2018) Adult-Onset Hepatocyte GH Resistance Promotes NASH in Male Mice, Without Severe Systemic Metabolic Dysfunction. Endocrinology 159:3761-3774
Wolf Greenstein, Abigail; Majumdar, Neena; Yang, Peng et al. (2017) Hepatocyte-specific, PPAR?-regulated mechanisms to promote steatosis in adult mice. J Endocrinol 232:107-121
Kineman, Rhonda D; Majumdar, Neena; Subbaiah, Papasani V et al. (2016) Hepatic PPAR? Is Not Essential for the Rapid Development of Steatosis After Loss of Hepatic GH Signaling, in Adult Male Mice. Endocrinology 157:1728-35
Liu, Zhongbo; Cordoba-Chacon, Jose; Kineman, Rhonda D et al. (2016) Growth Hormone Control of Hepatic Lipid Metabolism. Diabetes 65:3598-3609
Ibáñez-Costa, Alejandro; Córdoba-Chacón, José; 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
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 ?-cell mass. Growth Horm IGF Res 25:189-95
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
Luque, Raúl M; Córdoba-Chacón, José; Ibáñez-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
Gahete, Manuel D; Córdoba-Chacón, José; 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; Pokala, Naveen K et al. (2014) Long- but not short-term adult-onset, isolated GH deficiency in male mice leads to deterioration of ?-cell function, which cannot be accounted for by changes in ?-cell mass. Endocrinology 155:726-35

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