Effect of Increased Free Fatty Acids on Leptin Function

Differential Effects of Oral and Intravenous Lipid Administration on Leptin Signaling

Status

Completed

Phases

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01520454

Enrollment

Registered

2012-01-30

Start date

2011-11-30

Completion date

2016-12-31

Last updated

2018-05-11

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Leptin Resistance, Obesity

Keywords

Leptin resistance, Free fatty acids, Lipotoxicity

Brief 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.

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.

Interventions

DRUGSaline

IV saline at 0.83 mL/kg/hr for six hours

DRUGIntralipid

Intralipid in either low-dose or high dose (10% vs. 20%) at 0.83 mL/kr/hr for six hours

DIETARY_SUPPLEMENTWater

Water by mouth

DIETARY_SUPPLEMENToral fat

Soybean oil by mouth at 1.25 g/kg x 2 doses

DRUGHeparin

Heparin bolus of 1000 units followed by 800 u/hr, adjust per partial thromboplastin time (PTT), for 5.5 hours

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

BASIC_SCIENCE

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 65 Years

Healthy volunteers

Yes

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.

Design outcomes

Primary

Measure	Time frame	Description
Change in Circulating Glucagon-like Peptide-1 (GLP-1) Levels	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	Baseline to 6 hours	The GIP AUC fwas calculated from baseline to six hours
Change in Circulating Ghrelin Levels	Baseline to 6 hours	The Ghrelin AUC was calculated from baseline to six hours
Change in Circulating Peptide Tyrosine Tyrosine (PYY) Levels	Baseline to 6 hours	The PYY AUC was calculated from baseline to six hours

Secondary

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

Countries

United States

Participant flow

Participants by arm

Arm	Count
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	9
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	6
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	5
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	6
Total	26

Baseline characteristics

Characteristic	Placebo	High Dose Fat Solution	Low Dose Fat Solution	Oral Fat	Total
Age, Customized	35.3 years	29.1 years	48.6 years	27.6 years	35.2 years
Sex: Female, Male Female	2 Participants	1 Participants	1 Participants	3 Participants	7 Participants
Sex: Female, Male Male	7 Participants	5 Participants	4 Participants	3 Participants	19 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —
other Total, other adverse events	0 / 9	0 / 6	0 / 5	0 / 6
serious Total, serious adverse events	0 / 9	0 / 6	0 / 5	0 / 6