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)
Type
Research Project (R01)
Project #
5R01DK094483-04
Application #
8712481
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Laughlin, Maren R
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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
Magkos, Faidon; Smith, Gordon I; Reeds, Dominic N et al. (2014) One day of overfeeding impairs nocturnal glucose but not fatty acid homeostasis in overweight men. Obesity (Silver Spring) 22:435-40
Smith, Gordon I; Reeds, Dominic N; Okunade, Adewole L et al. (2014) Systemic delivery of estradiol, but not testosterone or progesterone, alters very low density lipoprotein-triglyceride kinetics in postmenopausal women. J Clin Endocrinol Metab 99:E1306-10
Smith, Gordon I; Magkos, Faidon; Reeds, Dominic N et al. (2013) One day of mixed meal overfeeding reduces hepatic insulin sensitivity and increases VLDL particle but not VLDL-triglyceride secretion in overweight and obese men. J Clin Endocrinol Metab 98:3454-62