Metabolic dysfunction (e.g., insulin resistance, diabetes and dyslipidemia) and certain types of cancer (e.g., colon cancer) are important complications associated with obesity. Weight loss can improve or even normalize metabolic function in obese persons, and has been shown to decrease colon cancer risk by reducing cell proliferation rates in rodent models. However, weight loss decreases muscle mass and bone mineral density, which can have adverse clinical effects in susceptible subjects such as postmenopausal women because they are already at increased risk for sarcopenia, impaired physical function and osteoporosis. It has been proposed that increasing protein intake during calorie restriction (CR) could ameliorate the adverse effects of CR on the musculoskeletal system, because of the anabolic effect of protein on muscle and bone metabolism. However, it is also possible that increased protein intake will impair insulin sensitivity by activating mammalian target of rapamycin (mTOR) signaling and stimulate cell proliferation in the colon by increasing circulating growth factors. Accordingly, the overall purpose of this proposal is to perform a 9-month randomized controlled trial to determine whether an 8%-10% body weight loss induced by CR alone or CR with protein supplementation has beneficial or harmful effects on multi-organ (liver, muscle, adipose tissue) insulin sensitivity, colonocyte proliferation, muscle mass and function, and bone mineral density and bone architecture in obese, postmenopausal women. The information gained from this work will fill important gaps in our knowledge that could affect clinical practice and weight management dietary guidelines.

Public Health Relevance

The purpose of this project is to provide a comprehensive evaluation of the health benefits of calorie restriction alone and calorie restriction with protein supplementation in obese subjects. Calorie restriction and weight loss has many health benefits but decreases muscle mass and bone mineral density. It has been proposed that increasing protein intake during calorie restriction could ameliorate the adverse effects on the musculoskeletal system. However, protein supplementation could cause insulin resistance and increase the risk for cancer. Accordingly, we will evaluate the effects of calorie restriction and calorie restriction with protein supplementation on colonocyte proliferation rate (colon cancer risk), insulin action (diabetes risk) and muscle and bone health. The information gained from this work will fill important gaps in our knowledge that could affect clinical practice and weight management dietary guidelines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK094483-03
Application #
8541011
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Laughlin, Maren R
Project Start
2011-09-21
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
3
Fiscal Year
2013
Total Cost
$485,693
Indirect Cost
$166,158
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Smith, Gordon I; Yoshino, Jun; Kelly, Shannon C et al. (2016) High-Protein Intake during Weight Loss Therapy Eliminates the Weight-Loss-Induced Improvement in Insulin Action in Obese Postmenopausal Women. Cell Rep 17:849-861
Smith, Gordon I; Mittendorfer, Bettina (2016) Sexual dimorphism in skeletal muscle protein turnover. J Appl Physiol (1985) 120:674-82
Mittendorfer, Bettina; Yoshino, Mihoko; Patterson, Bruce W et al. (2016) VLDL Triglyceride Kinetics in Lean, Overweight, and Obese Men and Women. J Clin Endocrinol Metab 101:4151-4160
Chondronikola, M; Harris, L L S; Klein, S (2016) Bariatric surgery and type 2 diabetes: are there weight loss-independent therapeutic effects of upper gastrointestinal bypass? J Intern Med 280:476-486
Smith, Gordon I; Mittendorfer, Bettina (2015) Response to Comment on Smith et al. Protein ingestion induces muscle insulin resistance independent of leucine-mediated mTOR activation. Diabetes 2015;64:1555-1563. Diabetes 64:e11
Smith, Gordon I; Patterson, Bruce W; Klein, Seth J et al. (2015) Effect of hyperinsulinaemia-hyperaminoacidaemia on leg muscle protein synthesis and breakdown: reassessment of the two-pool arterio-venous balance model. J Physiol 593:4245-57
Smith, Gordon I; Yoshino, Jun; Stromsdorfer, Kelly L et al. (2015) Protein Ingestion Induces Muscle Insulin Resistance Independent of Leucine-Mediated mTOR Activation. Diabetes 64:1555-63
Su, Xiong; Magkos, Faidon; Zhou, Dequan et al. (2015) Adipose tissue monomethyl branched-chain fatty acids and insulin sensitivity: Effects of obesity and weight loss. Obesity (Silver Spring) 23:329-34
Smith, Gordon I; Mittendorfer, Bettina (2015) Slimming down in old age. Am J Clin Nutr 101:247-8
Smith, Gordon I; Yoshino, Jun; Reeds, Dominic N et al. (2014) Testosterone and progesterone, but not estradiol, stimulate muscle protein synthesis in postmenopausal women. J Clin Endocrinol Metab 99:256-65

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