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Effect of Increased Free Fatty Acids on Leptin Function

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Christos Mantzoros, Beth Israel Deaconess Medical Center
ClinicalTrials.gov Identifier:
NCT01520454
First received: January 4, 2012
Last updated: March 16, 2017
Last verified: March 2017
January 4, 2012
March 16, 2017
November 2011
December 2013   (Final data collection date for primary outcome measure)
  • Change in Circulating Glucagon-like Peptide-1 (GLP-1) Levels [ Time Frame: Baseline to 6 hours ]
    The GLP-1 area under the curve (AUC) was calculated from baseline to six hours
  • Change in Circulating Gastric Inhibitory Polypeptide (GIP) Levels [ Time Frame: Baseline to 6 hours ]
    The GIP AUC fwas calculated from baseline to six hours
  • Change in Circulating Ghrelin Levels [ Time Frame: Baseline to 6 hours ]
    The Ghrelin AUC was calculated from baseline to six hours
  • Change in Circulating Peptide Tyrosine Tyrosine (PYY) Levels [ Time Frame: Baseline to 6 hours ]
    The PYY AUC was calculated from baseline to six hours
Change in intracellular messengers of leptin signaling [ Time Frame: Baseline to 6 hours ]
We will look at the change from baseline to +6 hours of a range of intracellular messengers associated with leptin signaliong, most prominently STAT3/pSTAT3 ratio.
Complete list of historical versions of study NCT01520454 on ClinicalTrials.gov Archive Site
  • Change in Circulating Glucose Levels [ Time Frame: Baseline to 6 hours ]
    The Glucose AUC was calculated from baseline to six hours
  • Change in Circulating Insulin Levels [ Time Frame: Baseline to 6 hours ]
    The Insulin AUC was calculated from baseline to six hours
  • Change in Circulating Leptin Levels [ Time Frame: Baseline to 6 hours ]
    The Leptin AUC was calculated from baseline to six hours
  • Change in Circulating Adiponectin Levels [ Time Frame: Baseline to 6 hours ]
    The Adiponectin AUC was calculated from baseline to six hours
  • Phosphorylation of STAT3 Pathways Downstream of Leptin After Lipid Administration [ Time Frame: Baseline to 6 hours ]

    Intracellular signaling mechanisms downstream of leptin (particularly the STAT3 pathway) in response to lipid administration as represented by phosphorylation (pSTAT3).

    The analysis unfortunately can not be performed due to technical reasons.

  • Change in circulating levels of gut hormones (GLP-1, GIP, ghrelin, PYY) [ Time Frame: Baseline to 6 hours ]
    We will assess the change from baseline to six hours in these gut-secreted hormones and compare between different intervention groups.
  • Change in circulating hormone levels [ Time Frame: Baseline to 6 hours ]
    We will assess the change from baseline to 6 hours in a range of standard hormones including insulin, glucose, thyroid hormones, growth hormones, etc. as well as leptin and other adipokines. We will compare the different interventional groups.
Not Provided
Not Provided
 
Effect of Increased Free Fatty Acids on Leptin Function
Differential Effects of Oral and Intravenous Lipid Administration on Leptin Signaling

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.

Interventional
Not Provided
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Basic Science
  • Obesity
  • Leptin Resistance
  • Drug: Saline
    IV saline at 0.83 mL/kg/hr for six hours
  • Drug: Intralipid
    Intralipid in either low-dose or high dose (10% vs. 20%) at 0.83 mL/kr/hr for six hours
    Other Name: intravenous lipids
  • Dietary Supplement: Water
    Water by mouth
  • Dietary Supplement: oral fat
    Soybean oil by mouth at 1.25 g/kg x 2 doses
    Other Name: soybean oil
  • Drug: Heparin
    Heparin bolus of 1000 units followed by 800 u/hr, adjust per partial thromboplastin time (PTT), for 5.5 hours
    Other Name: anti coated
  • Placebo Comparator: Placebo
    IV saline with heparin, oral water
    Interventions:
    • Drug: Saline
    • Dietary Supplement: Water
    • Drug: Heparin
  • Experimental: High dose fat solution
    Intralipid at high dose, with heparin and PO water
    Interventions:
    • Drug: Intralipid
    • Dietary Supplement: Water
    • Drug: Heparin
  • Experimental: Low dose fat solution
    Low dose IV Intralipid with heparin and PO water
    Interventions:
    • Drug: Intralipid
    • Dietary Supplement: Water
    • Drug: Heparin
  • Experimental: Oral fat
    Oral fat load with IV saline
    Interventions:
    • Drug: Saline
    • Dietary Supplement: Water
    • Dietary Supplement: oral fat
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
26
December 2016
December 2013   (Final data collection date for primary outcome measure)

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.
Sexes Eligible for Study: All
18 Years to 65 Years   (Adult)
Yes
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT01520454
2009P000370
No
Not Provided
Not Provided
Christos Mantzoros, Beth Israel Deaconess Medical Center
Beth Israel Deaconess Medical Center
Not Provided
Principal Investigator: Christos S Mantzoros, MD, DSc Beth Israel Deaconess Medical Center
Beth Israel Deaconess Medical Center
March 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP