effect of increased free fatty acids on leptin function

Conditions: Obesity; Leptin Resistance

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.

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.

Eligibility criteria:
inclusion criteria: * age 18-65 exclusion criteria: 1. subjects with a history of any illness, other than obesity, that may affect insulin sensitivity (anemia, infectious diseases, renal or hepatic failure, uncontrolled hypertension, cancer, lymphoma, chronic inflammatory conditions such as inflammatory bowel disease and rheumatoid arthritis, states of cortisol or growth hormone excess, alcoholism or drug abuse, and eating disorders). 2. history of diabetes mellitus. 3. subjects taking any medications that are known to influence glucose metabolism such as glucocorticoids will also be excluded. we will screen for these conditions by means of a detailed history and review of systems and physical examination (see below). 4. subjects taking any medications known to affect lipids such as statins will also be excluded. we will screen for these similar to above. 5. cholesterol greater or equal to 250 mg/dl and/or triglyceride levels greater than 500 mg/dl at the time of screening, as determined by laboratory testing. 6. subjects who have a known history of anaphylaxis or anaphylactoid-like reactions or who have a known hypersensitivity to anesthetic agents such as lidocaine or marcaine will be excluded from the study. 7. hypersensitivity to fat emulsion or any component of the formulation; severe egg or legume (soybean) allergies; pathologic hyperlipidemia, lipoid nephrosis, acute pancreatitis associated with hyperlipemia. 8. hypersensitivity to heparin or any component of the formulation 9. severe thrombocytopenia, uncontrolled active bleeding, disseminated intravascular coagulation (dic); suspected intracranial hemorrhage. 10. subjects with a history of bleeding dyscrasia, poor wound healing or any medical condition precluding supine position will be excluded from the study. 11. unable to follow study protocol or any condition that in the opinion of the investigator makes the subject unsuitable for the study. 12. pregnancy 13. prior history of gastrectomy, gastric bypass surgery, or other weight loss surgery.

Keywords: leptin resistance free fatty acids lipotoxicity