Effect of High Fat Diet on Muscle Metabolism
Condition: Diabetes
Study type: Interventional

Summary: 
      Skeletal muscle burns a significant amount of the fat and sugar that circulates in the blood
      stream. Ideally, when sugar is elevated in the blood stream, the muscle will either use it to
      make new energy or store it for later use. Likewise, for fatty acids. Skeletal muscle of
      obese and diabetic humans has been shown to inadequately use either sugar or fatty acids when
      they increase in the blood stream, and this has been termed metabolic inflexibility. The
      cause of metabolic inflexibility is not known, but it is believed that eating more fat than
      the body needs for energy may be a contributing factor. Metabolic inflexibility in skeletal
      muscle is bad because if the muscle does not use the sugar or fat, it will be stored
      elsewhere in the body and potentially lead to obesity and the resistance to insulin. The
      investigators have performed a research study with nonobese, healthy humans during which we
      fed them a high fat diet for 5 days. Interesting, only 5 days of a high fat diet is
      sufficient to cause the skeletal muscle to become metabolically inflexible just like that
      observed in obese and diabetic humans. The investigators are proposing addition studies to
      feed healthy humans a high fat diet for 5 days in effort to better understand what causes
      metabolic flexibility. The investigators are speculating that a high fat diet causes the
      intestines to release a substance called endotoxin that causes muscle to become metabolically
      inflexible. The investigators will test this notion in our proposed studies.
    

Detailed description: 
      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.
    

Intervention name(s): High Saturated Fat Diet
Intervention type(s): Other
Intervention description(s): Prior to the high fat diet and after baseline testing, subjects will be asked to eat a standard diet to "lead-in" to the high fat diet condition. The diet will contain 55% of calories as carbohydrate, 30% as fat, and 15% as protein. The high fat diet will contain 50-60% of calories as fat, 20-30% as carbohydrate, and 10-20% as protein. Subjects will be provided with all of their meals throughout the study.
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: skeletal muscle, metabolism, physiology