Effect of High Fat Diet on Muscle Metabolism

Objective: To discern the potential mechanism(s) by which high saturated fat feeding disrupts normal skeletal muscle metabolism. Our working hypothesis is that high saturated fat feeding increases gut permeability and blood endotoxin, which elicits pro-inflammatory signaling in skeletal muscle and alters the normal adaptive response to a meal. Preliminary evidence using a model of acute (5 days), high saturated fat feeding, isocaloric to habitual intake, in healthy, non-obese humans is presented herein to support this hypothesis.

Background: The inability for skeletal muscle to adapt fuel oxidation to fuel availability is termed metabolic inflexibility, a well characterized feature of disease states such as obesity, metabolic syndrome, and type 2 diabetes (T2D). The mechanism(s) responsible for skeletal muscle metabolic inflexibility are not known. Recently, there has been growing interest in the role of gut permeability and blood endotoxin in the pathology of metabolic derangements associated with obesity and T2D. Rodent studies have revealed direct links between the gut microbiome and metabolic disease, as well as associations between elevated blood endotoxin and metabolic dysregulation, both at the whole body and tissue level. High fat feeding in rodents is known to elicit elevated levels of blood endotoxin, a phenomenon that is termed metabolic endotoxemia. In humans, obesity and T2D are associated with increased blood endotoxin and single meals have been shown to elevate blood endotoxin, but to date, there is no evidence in humans that high fat feeding results in metabolic endotoxemia. Moreover, there are no established links between gut permeability, metabolic endotoxemia, and skeletal muscle metabolic function in humans.

Approach. We are proposing to utilize a model of acute high fat feeding in healthy humans to study the interplay between gut function, blood endotoxin, and skeletal muscle pro-inflammatory signaling and metabolic adaptability. We will employ a two-week lead-in period, during which research participants will be fed prepared meals that are isocaloric to their habitual diet, followed by five days of high saturated fat feeding. The high saturated fat feeding period will consist of prepared meals that are isocaloric to habitual diet with a macronutrient composition of 50% fat (45% of which will be saturated fat), 35% carbohydrate, and 15% protein. Studying healthy, nonobese humans in this context is an innovative approach on two levels: 1) any confounding influences associated with metabolic disease (obesity, diabetes, or metabolic syndrome) are eliminated, e.g., insulin resistance, hyperlipidemia, impaired gut function, pre-existing metabolic dysfunction and inflammatory tone; and 2) the isocaloric feeding design negates the confounding influence of a positive energy balance and allows us to specifically examine the effects of acutely increasing dietary saturated fat.

Inclusion criteria

• Males, age 18-40 years; BMI between 20 and 30 kg/m2. Weight stable for previous 6 months (± 2.0kg).

Sedentary to recreationally active (≤ 3 days, 20 min/day of walking type exercise, no planned exercise other than leisure walking for transportation purposes).

Verbal and written informed consent

non-smoking

Approved for participation by Medical Director (Jose Rivero, M.D.)

Exclusion criteria

• 1. Past or current ischemic heart disease, stroke, respiratory disease, endocrine or metabolic disease, neurological disease, or hematological-oncological disease

• Family history of diabetes

• BMI > 30 kg/m2, blood pressure > 140/90 mmHg or antihypertensive medications, fasting glucose > 100 mg/dl, LDL cholesterol > 130 mg/dl, total cholesterol > 200 mg/dl, triglycerides > 250 mg/dl.

• Verbal and written informed consent

• Smoking, alcohol consumption > 2 servings/d, or taking medications (including but not limited to statins or other drugs with anti-inflammatory actions) or antioxidant vitamins or supplements, or know to affect carbohydrate or lipid metabolism.

• Total daily dietary fat consumption ≥ 35% and/or saturated fat consumption of ≥ 15%.