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Effect of Increased Free Fatty Acids on Leptin Function

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01520454
First Posted: January 30, 2012
Last Update Posted: April 26, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Christos Mantzoros, Beth Israel Deaconess Medical Center
  Purpose

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.


Condition Intervention
Obesity Leptin Resistance Drug: Saline Drug: Intralipid Dietary Supplement: Water Dietary Supplement: oral fat Drug: Heparin

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Differential Effects of Oral and Intravenous Lipid Administration on Leptin Signaling

Further study details as provided by Christos Mantzoros, Beth Israel Deaconess Medical Center:

Primary Outcome Measures:
  • 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


Secondary Outcome Measures:
  • 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.



Enrollment: 26
Study Start Date: November 2011
Study Completion Date: December 2016
Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Placebo
IV saline with heparin, oral water
Drug: Saline
IV saline at 0.83 mL/kg/hr for six hours
Dietary Supplement: Water
Water by mouth
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
Experimental: High dose fat solution
Intralipid at high dose, with heparin and PO water
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
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
Experimental: Low dose fat solution
Low dose IV Intralipid with heparin and PO water
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
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
Experimental: Oral fat
Oral fat load with IV saline
Drug: Saline
IV saline at 0.83 mL/kg/hr for six hours
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

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.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01520454


Locations
United States, Massachusetts
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02215
Sponsors and Collaborators
Beth Israel Deaconess Medical Center
Investigators
Principal Investigator: Christos S Mantzoros, MD, DSc Beth Israel Deaconess Medical Center
  More Information

Additional Information:
Responsible Party: Christos Mantzoros, Professor of Medicine, Beth Israel Deaconess Medical Center
ClinicalTrials.gov Identifier: NCT01520454     History of Changes
Other Study ID Numbers: 2009P000370
First Submitted: January 4, 2012
First Posted: January 30, 2012
Results First Submitted: December 29, 2015
Results First Posted: April 26, 2017
Last Update Posted: April 26, 2017
Last Verified: March 2017

Keywords provided by Christos Mantzoros, Beth Israel Deaconess Medical Center:
Leptin resistance
Free fatty acids
Lipotoxicity

Additional relevant MeSH terms:
Calcium heparin
Heparin
Soybean oil, phospholipid emulsion
Anticoagulants
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Fat Emulsions, Intravenous
Parenteral Nutrition Solutions
Pharmaceutical Solutions