Effect of Increased Free Fatty Acids on Leptin Function
Condition: Obesity; Leptin Resistance
Study type: Interventional

Summary: 
      Obese people have elevated levels of the hormone leptin. Despite this, they seem to be
      resistant to the effects of this hormone, which usually regulates appetite and energy
      expenditure. This is similar to what happens with insulin levels in the obese. Furthermore,
      the way lipid ingestion versus lipid infusion may impact novel molecules secreted by tissues
      commonly affected in insulin resistant states such as liver and muscle have not yet been
      studied.

      The aim of the present study is to investigate the effect of oral vs. different doses of IV
      lipid administration on molecular parameters related to glucose and energy homeostasis using
      a randomized, placebo-controlled design.

      Additionally, we will examine how increased free fatty acids (FFAs) my impact intracellular
      leptin signaling such as the STAT3 pathway.
    

Detailed description: 
      We propose to test our hypotheses by conducting a non-blinded, interventional study
      evaluating the effects of acute leptin administration on intracellular leptin signaling
      pathways after a 6 hour infusion period comparing an oral high fat meal, high fat lipid
      infusion, low fat lipid infusion, or placebo infusion (saline)iv lipid infusion, placebo
      (saline) and oral high fat meal. After a screening visit, study participation involves 1 meal
      pick-up visit, 1 overnight visit, and one 1 follow-up visit. Subjects will be randomized to
      one of 4 groups: an oral high fat meal, fat emulsion 20% infusion , fat emulsion 10%
      infusion, and a placebo (saline) infusion infusion and an oral high fat meal.

      We plan to screen 100 male and postmenopausal female subjects, with BMI greater than 18
      kg/m2, to consent 60 in order to have 32-48 evaluable subjects, 8-12 subjects per group,
      completing all parts of the study.

      The primary study outcome to be evaluated will be the changes in serum concentrations of
      glucose, hormones influencing metabolism such as insulin, fat-cell-secreted proteins such as
      leptin, molecules involved in metabolism such as free fatty acids (FFAs), and markers of
      inflammation such as interleukin (IL)-2 and interferon (IFN)-gamma.

      The secondary outcome will be to examine the impacts of increased FFAs on intracellular
      leptin signaling by phosphorylation of STAT3.
    

Intervention name(s): Saline; Intralipid; Water; oral fat; Heparin
Intervention type(s): Drug; Drug; Dietary Supplement; Dietary Supplement; Drug
Intervention description(s): IV saline at 0.83 mL/kg/hr for six hours; Intralipid in either low-dose or high dose (10% vs. 20%) at 0.83 mL/kr/hr for six hours; Water by mouth; Soybean oil by mouth at 1.25 g/kg x 2 doses; Heparin bolus of 1000 units followed by 800 u/hr, adjust per partial thromboplastin time (PTT), for 5.5 hours
Other intervention name(s): intravenous lipids; soybean oil; anti coated
Intervention MeSH terms: Heparin; Soybean oil, phospholipid emulsion
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Leptin resistance; Free fatty acids; Lipotoxicity