Saturated Fat Versus Monounsaturated Fat and Insulin Action
Condition: Obesity
Study type: Interventional

Summary: 
      High intakes of saturated fat are associated with diabetes. Our work has shown that the two
      most common fatty acids in the North American diet, palmitic acid (saturated fat) and oleic
      acid (monounsaturated fat) are metabolized differently and have opposite effects on fat
      burning. The proposed study will examine biochemical and molecular mechanisms for how a high
      saturated fat diet versus a low saturated fat/high monounsaturated fat diet alters the action
      of the hormone, insulin, in skeletal muscle.
    

Detailed description: 
      Palmitic acid (PA), impairs insulin sensitivity in skeletal muscle, and replacing PA in the
      diet with oleic acid (OA), a monounsaturated fatty acid (FA), may be beneficial. The first
      objective of this project is to understand the effects on lipid metabolism and skeletal
      muscle lipid composition, insulin signaling, and inflammatory signaling of two common
      variations in FA composition of the diet: (1) The typical intake of North America where PA
      and OA are present in equal proportions (HI PA diet). (2) The Mediterranean FA composition in
      which PA is much lower and OA much higher (HI OA diet). PA may induce insulin resistance in
      skeletal muscle cells via its accumulation in lipids within muscle cells and via activation
      of inflammatory signaling. The second objective of this project is to assess the hypothesis
      that a high intake of PA will down-regulate its own one-carbon (initial) oxidation, leading
      to increased inflammatory signaling and decreased insulin signaling. However, there is
      literature evidence that FA may induce defects in insulin signaling, if FA are not completely
      oxidized; therefore, the third objective is to assess the hypotheses that a high PA diet may
      decrease complete oxidation of FA and possibly accelerate initial FA oxidation. A
      double-masked, cross-over trial of the effects of a high PA diet versus a high OA/low PA diet
      in 16 overweight or obese subjects and 16 lean subjects (aged 18 - 40 yr) will be conducted
      to investigate the following Specific Aims:

        1. To test the hypothesis that increased intake of PA will cause a decreased rate of
           [1-13C]-PA oxidation and will be associated with: (a) increased inflammatory signaling,
           within the muscle and by peripheral blood mononuclear cells; (b) Decreased insulin
           signaling as characterized by decreased, whole body, peripheral insulin sensitivity
           (euglycemic/hyperinsulinemic clamp) and, in skeletal muscle, decreased phospho-AKT
           (Ser473), increased phospho-IRS-1 (Ser636/Ser639), decreased tyrosine phosphorylation of
           IRS-1, and decreased membrane content of GLUT4.

        2. To test the hypothesis that increased intake of PA will cause less complete
           mitochondrial fatty acid oxidation, perhaps associated with dysfunction of the TCA cycle
           and increased reactive oxygen species formation. This hypothesis will be tested by
           measuring whole body and muscle (upper limb) relative rates of oxidation of [13-13C]-PA
           and [1-13C]-PA and by determining the serum profile of acylcarnitines, the urine
           concentrations of organic acids, and muscle concentrations of protein carbonyls.

        3. To test the hypothesis that a high PA diet will lead to less complete oxidation of FA,
           less insulin signaling in skeletal muscle in response to a test meal, less whole body
           insulin sensitivity, increased dysfunction of the TCA cycle, and greater reactive oxygen
           species formation compared to the results obtained in obese versus lean humans.
    

Intervention name(s): High palmitate or high oleate diet.
Intervention type(s): Dietary Supplement
Intervention description(s): High palmitate diet composition: Fat, 40.4% kcal; palmitic acid, 16.0% kcal; oleic acid,16.2% kcal. High oleate diet composition: Fat, 40.1% kcal; palmitic acid, 2.4% kcal; oleic acid, 28.8% kcal
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: humans; lean; obese; saturated fat; monounsaturated fat; insulin sensitivity; inflammation; oxidant stress