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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo | Placebo Comparator | IV saline with heparin, oral water |
|
| High dose fat solution | Experimental | Intralipid at high dose, with heparin and PO water |
|
| Low dose fat solution | Experimental | Low dose IV Intralipid with heparin and PO water |
|
| Oral fat | Experimental | Oral fat load with IV saline |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Saline | Drug | IV saline at 0.83 mL/kg/hr for six hours |
| |
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Christos S Mantzoros, MD, DSc | Beth Israel Deaconess Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Beth Israel Deaconess Medical Center | Boston | Massachusetts | 02215 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 35961260 | Derived | 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. |
| Label | URL |
|---|---|
| Mantzoros Lab Home Page | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo | IV saline with heparin, oral water Saline: IV saline at 0.83 mL/kg/hr for six hours Water: Water by mouth Heparin: Heparin bolus of 1000 units followed by 800 u/hr, adjust per partial thromboplastin time (PTT), for 5.5 hours |
| FG001 | High Dose Fat Solution | Intralipid at high dose, with heparin and PO water Intralipid: Intralipid in either low-dose or high dose (10% vs. 20%) at 0.83 mL/kr/hr for six hours Water: Water by mouth Heparin: Heparin bolus of 1000 units followed by 800 u/hr, adjust per PTT, for 5.5 hours |
| FG002 | Low Dose Fat Solution | Low dose IV Intralipid with heparin and PO water Intralipid: Intralipid in either low-dose or high dose (10% vs. 20%) at 0.83 mL/kr/hr for six hours Water: Water by mouth Heparin: Heparin bolus of 1000 units followed by 800 u/hr, adjust per PTT, for 5.5 hours |
| FG003 | Oral Fat | Oral fat load with IV saline Saline: IV saline at 0.83 mL/kg/hr for six hours Water: Water by mouth oral fat: Soybean oil by mouth at 1.25 g/kg x 2 doses |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Placebo | IV saline with heparin, oral water Saline: IV saline at 0.83 mL/kg/hr for six hours Water: Water by mouth Heparin: Heparin bolus of 1000 units followed by 800 u/hr, adjust per PTT, for 5.5 hours |
| BG001 | High Dose Fat Solution |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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 | Areas under the curve are presented | Posted | Mean | Standard Deviation | pM*min | Baseline to 6 hours |
|
6 months
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Placebo | IV saline with heparin, oral water Saline: IV saline at 0.83 mL/kg/hr for six hours Water: Water by mouth Heparin: Heparin bolus of 1000 units followed by 800 u/hr, adjust per PTT, for 5.5 hours |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Christos Manztoros | Beth Israel Deaconess Medical Center | 617-667-8630 | cmantzor@bidmc.harvard.edu |
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| ID | Term |
|---|---|
| D009765 | Obesity |
| ID | Term |
|---|---|
| D050177 | Overweight |
| D044343 | Overnutrition |
| D009748 | Nutrition Disorders |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| D012965 | Sodium Chloride |
| C545823 | soybean oil, phospholipid emulsion |
| D014867 | Water |
| D018955 | CD36 Antigens |
| D013024 | Soybean Oil |
| D006493 | Heparin |
| ID | Term |
|---|---|
| D002712 | Chlorides |
| D006851 | Hydrochloric Acid |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
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| Intralipid |
| Drug |
Intralipid in either low-dose or high dose (10% vs. 20%) at 0.83 mL/kr/hr for six hours |
|
|
| Water | Dietary Supplement | Water by mouth |
|
| oral fat | Dietary Supplement | Soybean oil by mouth at 1.25 g/kg x 2 doses |
|
|
| Heparin | Drug | Heparin bolus of 1000 units followed by 800 u/hr, adjust per partial thromboplastin time (PTT), for 5.5 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 |
Intralipid at high dose, with heparin and PO water Intralipid: Intralipid in either low-dose or high dose (10% vs. 20%) at 0.83 mL/kr/hr for six hours Water: Water by mouth Heparin: Heparin bolus of 1000 units followed by 800 u/hr, adjust per PTT, for 5.5 hours |
| BG002 | Low Dose Fat Solution | Low dose IV Intralipid with heparin and PO water Intralipid: Intralipid in either low-dose or high dose (10% vs. 20%) at 0.83 mL/kr/hr for six hours Water: Water by mouth Heparin: Heparin bolus of 1000 units followed by 800 u/hr, adjust per PTT, for 5.5 hours |
| BG003 | Oral Fat | Oral fat load with IV saline Saline: IV saline at 0.83 mL/kg/hr for six hours Water: Water by mouth oral fat: Soybean oil by mouth at 1.25 g/kg x 2 doses |
| BG004 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| OG002 | Low Dose Fat Solution | Low dose IV Intralipid with heparin and PO water Intralipid: Intralipid in either low-dose or high dose (10% vs. 20%) at 0.83 mL/kr/hr for six hours Water: Water by mouth Heparin: Heparin bolus of 1000 units followed by 800 u/hr, adjust per PTT, for 5.5 hours |
| OG003 | Oral Fat | Oral fat load with IV saline Saline: IV saline at 0.83 mL/kg/hr for six hours Water: Water by mouth oral fat: Soybean oil by mouth at 1.25 g/kg x 2 doses |
|
|
| Primary | Change in Circulating Gastric Inhibitory Polypeptide (GIP) Levels | The GIP AUC fwas calculated from baseline to six hours | Areas under the curve are presented | Posted | Mean | Standard Deviation | pM*min/ml | Baseline to 6 hours |
|
|
|
| Primary | Change in Circulating Ghrelin Levels | The Ghrelin AUC was calculated from baseline to six hours | Areas under the curve are presented | Posted | Mean | Standard Deviation | pg*min/ml | Baseline to 6 hours |
|
|
|
| Primary | Change in Circulating Peptide Tyrosine Tyrosine (PYY) Levels | The PYY AUC was calculated from baseline to six hours | Areas under the curve are presented | Posted | Mean | Standard Deviation | pg*min/ml | Baseline to 6 hours |
|
|
|
| Secondary | Change in Circulating Glucose Levels | The Glucose AUC was calculated from baseline to six hours | Areas Under the Curve are presented | Posted | Mean | Standard Deviation | mg*min/dl | Baseline to 6 hours |
|
|
|
| Secondary | Change in Circulating Insulin Levels | The Insulin AUC was calculated from baseline to six hours | Areas Under the Curve are presented | Posted | Mean | Standard Deviation | mU*min/ml | Baseline to 6 hours |
|
|
|
| Secondary | Change in Circulating Leptin Levels | The Leptin AUC was calculated from baseline to six hours | Areas Under the Curve are presented | Posted | Mean | Standard Deviation | ng*min/ml | Baseline to 6 hours |
|
|
|
| Secondary | Change in Circulating Adiponectin Levels | The Adiponectin AUC was calculated from baseline to six hours | Areas Under the Curve are presented | Posted | Mean | Standard Deviation | ng*min/ml | Baseline to 6 hours |
|
|
|
| Secondary | 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). | The analysis unfortunately can not be performed due to technical reasons as STAT3 was not able to be measured in the samples/not enough volume was left to perform the appropriate tests after trouble-shooting. | Posted | Baseline to 6 hours |
|
|
| 0 |
| 9 |
| 0 |
| 9 |
| EG001 | High Dose Fat Solution | Intralipid at high dose, with heparin and PO water Intralipid: Intralipid in either low-dose or high dose (10% vs. 20%) at 0.83 mL/kr/hr for six hours Water: Water by mouth Heparin: Heparin bolus of 1000 units followed by 800 u/hr, adjust per PTT, for 5.5 hours | 0 | 6 | 0 | 6 |
| EG002 | Low Dose Fat Solution | Low dose IV Intralipid with heparin and PO water Intralipid: Intralipid in either low-dose or high dose (10% vs. 20%) at 0.83 mL/kr/hr for six hours Water: Water by mouth Heparin: Heparin bolus of 1000 units followed by 800 u/hr, adjust per PTT, for 5.5 hours | 0 | 5 | 0 | 5 |
| EG003 | Oral Fat | Oral fat load with IV saline Saline: IV saline at 0.83 mL/kg/hr for six hours Water: Water by mouth oral fat: Soybean oil by mouth at 1.25 g/kg x 2 doses | 0 | 6 | 0 | 6 |
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| D001835 |
| Body Weight |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D017670 |
| Sodium Compounds |
| D006878 | Hydroxides |
| D000468 | Alkalies |
| D000838 | Anions |
| D007477 | Ions |
| D004573 | Electrolytes |
| D010087 | Oxides |
| D017601 | Oxygen Compounds |
| D010980 | Platelet Membrane Glycoproteins |
| D008562 | Membrane Glycoproteins |
| D006023 | Glycoproteins |
| D006001 | Glycoconjugates |
| D002241 | Carbohydrates |
| D050612 | Fatty Acid Transport Proteins |
| D026901 | Membrane Transport Proteins |
| D002352 | Carrier Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D008565 | Membrane Proteins |
| D011956 | Receptors, Cell Surface |
| D011971 | Receptors, Immunologic |
| D051122 | Scavenger Receptors, Class B |
| D051116 | Receptors, Scavenger |
| D011973 | Receptors, LDL |
| D018110 | Receptors, Lipoprotein |
| D004042 | Dietary Fats, Unsaturated |
| D004041 | Dietary Fats |
| D005223 | Fats |
| D008055 | Lipids |
| D005224 | Fats, Unsaturated |
| D010938 | Plant Oils |
| D009821 | Oils |
| D028321 | Plant Preparations |
| D001688 | Biological Products |
| D045424 | Complex Mixtures |
| D005502 | Food |
| D000066888 | Diet, Food, and Nutrition |
| D010829 | Physiological Phenomena |
| D019602 | Food and Beverages |
| D006025 | Glycosaminoglycans |
| D011134 | Polysaccharides |