Abdominal obesity is associated with significant morbidity, including hypertension, dyslipidemia, insulin resistance and increased cardiovascular disease risk. Growth hormone (GH), a pituitary gland derived anabolic hormone which stimulates lipolysis, is reduced in association with excess abdominal obesity. The reduced GH associated with obesity can be normalized with weight loss, suggesting a relative or functional deficiency. Relative GH deficiency of obesity is associated with increased cardio-metabolic risk independent of traditional cardiovascular risk factors. Furthermore, treatment of obese subjects with GH results in loss of visceral adiposity and improvement in cardio-metabolic risk markers, suggesting a causal association between relative GH deficiency and obesity-associated cardio-metabolic risk. As GH stimulates lipolysis, and lipolysis/2- oxidation is primarily a function of mitochondria, the potent effect of GH to oxidize fat suggests potential effects of GH on mitochondrial function. However, the relationship between GH and mitochondrial function has yet to be clarified in humans, and it is not yet known if GH affects skeletal muscle mitochondrial number, morphology or function. We hypothesize that reduced GH secretion associated with obesity contributes to defects in mitochondrial function which can be improved by normalizing endogenous GH. To evaluate the relationship between reduced GH associated with obesity and mitochondrial dysfunction, the candidate will be mentored by internationally recognized experts in clinical metabolic/physiology research, assessment of in vivo mitochondrial function, and molecular biology and microscopy techniques. The K23 award will support both formal and informal training designed specifically to provide the necessary skills in translational human research which will include training in clinical research methods specific to evaluation of obesity, GH, metabolism, mitochondrial biology and cardiovascular disease risk assessment, biostatistics, and ethics of human research through the Harvard School of Public Health, Massachusetts General Hospital, and scientific workshops, symposia and meetings. Daily interactions with the candidates'mentors and colleagues will further enhance his training and career development. The combination of the candidates'prior back ground in basic science research and his growing expertise in clinical investigation places him in a unique position to develop a translational research career which will both deepen our understanding of obesity and result in development of novel therapies for obesity and its associated complications.

Public Health Relevance

Metabolic and cardiovascular complications of obesity have increased in parallel with the obesity epidemic in recent years. However, non-surgical treatments for obesity are only minimally efficacious and options remain sparse. Given the known role of growth hormone in stimulating lipolysis and the recognized role of mitochondria in mediating 2-oxidation, manipulations of the growth hormone axis to target mitochondrial function is an intriguing prospect for the treatment of obesity and its co-morbidities.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Mentored Patient-Oriented Research Career Development Award (K23)
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Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
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Hyde, James F
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Massachusetts General Hospital
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Makimura, Hideo; Stanley, Takara L; Suresh, Caroline et al. (2016) Metabolic Effects of Long-Term Reduction in Free Fatty Acids With Acipimox in Obesity: A Randomized Trial. J Clin Endocrinol Metab 101:1123-33
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Makimura, Hideo; Murphy, Caitlin A; Feldpausch, Meghan N et al. (2014) The effects of tesamorelin on phosphocreatine recovery in obese subjects with reduced GH. J Clin Endocrinol Metab 99:338-43
Faje, Alexander T; Nachtigall, Lisa; Wexler, Deborah et al. (2013) Central diabetes insipidus: a previously unreported side effect of temozolomide. J Clin Endocrinol Metab 98:3926-31
Makimura, Hideo; Feldpausch, Meghan N; Stanley, Takara L et al. (2012) Reduced growth hormone secretion in obesity is associated with smaller LDL and HDL particle size. Clin Endocrinol (Oxf) 76:220-7
Zanni, Markella V; Burdo, Tricia H; Makimura, Hideo et al. (2012) Relationship between monocyte/macrophage activation marker soluble CD163 and insulin resistance in obese and normal-weight subjects. Clin Endocrinol (Oxf) 77:385-90

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