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.

Study Overview

• Status: Completed
• Conditions: Obesity; Leptin Resistance
• Intervention / Treatment: Drug: Saline; Dietary supplement: Water; Drug: Heparin; Drug: Intralipid; Dietary supplement: oral fat

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.

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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 Names: anti coated
Experimental: High dose fat solution; Intralipid at high dose, with heparin and PO water	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 Names: anti coated; Drug: Intralipid; Intralipid in either low-dose or high dose (10% vs. 20%) at 0.83 mL/kr/hr for six hours; Other Names: intravenous lipids
Experimental: Low dose fat solution; Low dose IV Intralipid with heparin and PO water	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 Names: anti coated; Drug: Intralipid; Intralipid in either low-dose or high dose (10% vs. 20%) at 0.83 mL/kr/hr for six hours; Other Names: intravenous lipids
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 Names: soybean oil

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Circulating Glucagon-like Peptide-1 (GLP-1) Levels	The GLP-1 area under the curve (AUC) was calculated from baseline to six hours	Baseline to 6 hours
Change in Circulating Gastric Inhibitory Polypeptide (GIP) Levels	The GIP AUC fwas calculated from baseline to six hours	Baseline to 6 hours
Change in Circulating Ghrelin Levels	The Ghrelin AUC was calculated from baseline to six hours	Baseline to 6 hours
Change in Circulating Peptide Tyrosine Tyrosine (PYY) Levels	The PYY AUC was calculated from baseline to six hours	Baseline to 6 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Circulating Glucose Levels	The Glucose AUC was calculated from baseline to six hours	Baseline to 6 hours
Change in Circulating Insulin Levels	The Insulin AUC was calculated from baseline to six hours	Baseline to 6 hours
Change in Circulating Leptin Levels	The Leptin AUC was calculated from baseline to six hours	Baseline to 6 hours
Change in Circulating Adiponectin Levels	The Adiponectin AUC was calculated from baseline to six hours	Baseline to 6 hours
Phosphorylation of STAT3 Pathways Downstream of Leptin After Lipid Administration	Intracellular signaling mechanisms downstream of leptin (particularly the STAT3 pathway) in response to lipid administration as represented by phosphorylation (pSTAT3).	Baseline to 6 hours

Collaborators and Investigators

• Sponsor: Beth Israel Deaconess Medical Center
• Investigators: Principal Investigator: Christos S Mantzoros, MD, DSc, Beth Israel Deaconess Medical Center

Publications and helpful links

General Publications

• Perakakis N, Kokkinos A, Angelidi AM, Tsilingiris D, Gavrieli A, Yannakoulia M, Tentolouris N, Mantzoros CS. Circulating levels of five proglucagon-derived peptides in response to intravenous or oral glucose or lipids and to a mixed-meal in subjects with normal weight, overweight, and obesity. Clin Nutr. 2022 Sep;41(9):1969-1976. doi: 10.1016/j.clnu.2022.07.001. Epub 2022 Jul 19.

Helpful Links

• Mantzoros Lab Home Page

Study record dates

Study Major Dates

• Study Start: November 1, 2011
• Primary Completion (Actual): December 1, 2013
• Study Completion (Actual): December 1, 2016

Study Registration Dates

• First Submitted: January 4, 2012
• First Submitted That Met QC Criteria: January 27, 2012
• First Posted (Estimate): January 30, 2012

Study Record Updates

• Last Update Posted (Actual): May 11, 2018
• Last Update Submitted That Met QC Criteria: May 8, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Keywords: Lipotoxicity; Free fatty acids; Leptin resistance
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Pharmaceutical Solutions; Parenteral Nutrition Solutions; Fat Emulsions, Intravenous; Heparin; Soybean oil, phospholipid emulsion
• Other Study ID Numbers: 2009P000370