Nutrition, Exercise and Muscle Metabolism in Obesity
Nutrition, Exercise and Muscle Metabolism in Obesity
Obesity is a major public health issue and its association with insulin resistance greatly
 increases risks for cardiovascular disease and type 2 diabetes. Exercise training is
 recommended for obese populations, but longitudinal studies indicate aerobic exercise
 training in obese individuals in the absence of weight loss has minimal impact on insulin
 resistance. High turnover of fat stored within muscle cells (i.e., intramyocellular
 triglyceride) during exercise and elevated muscle fitness (i.e., muscle oxidative capacity)
 are key features of the enhanced insulin sensitivity observed in endurance-trained
 individuals. It could be that longitudinal studies of exercise training in obese individuals
 failed to sufficiently stimulate intramyocellular triglyceride turnover during exercise and
 muscle oxidative adaptation as a result of failure to consider the impact of recent nutrition
 within their study designs. Performing exercise in the fed vs. fasted state can blunt these
 exercise responses in non-obese individuals. The researchers will investigate the hypothesis
 that an acute bout of aerobic exercise performed in the overnight-fasted versus fed-state can
 stimulate greater intramyocellular triglyceride utilization during exercise and enhanced
 expression of genes related to muscle oxidative adaptation in obese individuals. The expected
 outcomes will help to determine if exercising in the fasted state could be used to optimise
 metabolic adaptation to training in obese individuals. The future impact of this research
 could be the recommendation of a simple nutritional strategy considering meal timing to
 enhance the effects of aerobic exercise training in obese individuals, with potential
 long-term benefits for reducing insulin resistance and cardio-metabolic disease risk.
Two thirds of the adult US population is overweight or obese and the prevention and treatment
 of obesity is a key priority due to the strain on societal health, well-being and economic
 prosperity. Obesity is associated with insulin resistance characterized by a reduced ability
 of insulin to stimulate glucose uptake into skeletal muscle and by hyperglycaemia. Obesity
 and insulin resistance are major risk factors for cardiovascular disease and type 2 diabetes.
 Weight loss through caloric restriction and increasing physical activity levels are the
 mainstay of non-surgical/pharmacological treatment for obesity. Weight loss can reduce
 insulin resistance although sustainable weight loss is difficult to achieve. Physical
 activity can help with weight maintenance but perhaps surprisingly, carefully controlled
 longitudinal studies in obese patients indicate aerobic exercise training in the absence of
 weight loss has no or at best modest impact on peripheral insulin resistance.

 One mechanism by which regular aerobic exercise training ensures high peripheral insulin
 sensitivity in endurance trained individuals is via stimulation of intramyocellular
 triglyceride turnover and muscle fat oxidation, which maintains low muscle levels of fatty
 acid metabolites known to interfere with insulin-stimulated muscle glucose uptake (e.g.,
 fatty acyl CoA, diacyglycerols, ceramides). Indirect evidence suggests intramyocellular
 triglyceride can be utilized as fuel during aerobic exercise in obese individuals, at least
 in the overnight-fasted state. However, the influence of overnight-fasted vs. fed-state
 exercise on intramyocellular triglyceride utilization and muscle oxidative adaptation has not
 been studied in obesity. This is important to study as fed-state exercise, as compared to
 overnight-fasted exercise, blunts exercise-associated increases in intramyocellular
 triglyceride utilization, oxidative gene expression, long-term adaptation of muscle oxidative
 capacity and resistance to high fat diet induced impairments in oral glucose tolerance in
 lean individuals.

 Thus, the presence or timing of recent nutrition with respect to exercise could be a critical
 factor explaining the inability of aerobic exercise training per se to improve peripheral
 insulin sensitivity in longitudinal studies in obese populations. Exercising in the
 overnight-fasted state could optimize metabolic adaptation to training in obese individuals
 with long-term benefits for reduced insulin resistance and cardio-metabolic disease risk.
-  Anthropometry/Body Size:

 i. Overweight (White European populations, BMI 25-29.9 kg/m2 or Asian populations, BMI
 23-27.4 kg/m2) and have a high waist circumference (European, Sub-Saharan Africans and
 Eastern Mediterranean and middle east [Arab] men ≥ 94 cm [37 inches], women ≥ 80 cm
 [31.5 inches]; South Asian, Chinese, Japanese, and ethnic south and central Americans
 men ≥ 90 cm [35 inches], women ≥ 80 cm [31.5 inches]) or ii. Class I obesity (White
 European populations, BMI 30-34.9 kg/m2 or Asian populations, BMI 27.5-35 kg/m2).

 -  Weight stable i.e. (±2 kg) for >3 months before enrolment

 -  Sedentary i.e. no regular engagement in physical activity

 -  Diagnosis and general health: Good general health defined as no known cardiovascular
 or metabolic disease

 -  Compliance: understands and is willing, able and likely to comply with all study
 procedures and restrictions

 -  Consent: demonstrates understanding of the study and willingness to participate as
 evidenced by voluntary written informed consent.

 Exclusion Criteria:

 -  Answering "YES" to any question on the Screening Form

 -  Hypertension (≥140/90 mmHg)

 -  Any ECG Abnormalities

 -  Current participation in another clinical study

 -  Current or recent smoker (last 30 days)

 -  Past history of substance abuse, engagement in uncommon eating practices (e.g.,
 sustained periods of fasting) and taking prescription or non-prescription medication
 (e.g., beta-blockers, insulin or thyroxine) or supplements that may influence normal
 metabolic responses.

 -  Participants who have previously (within 5 years of the present study) had 4 or more
 muscle biopsies obtained from the thigh quadriceps region will be ineligible