The effects of recombinant human leptin on visceral fat, dyslipidemia, and insulin resistance in patients with human immunodeficiency virus-associated lipoatrophy and hypoleptinemia.
BACKGROUND
Leptin deficiency is associated with dyslipidemia and insulin resistance in animals and humans with lipoatrophy; leptin replacement ameliorates these abnormalities.


OBJECTIVE
The objective of the study was to evaluate the effects of leptin therapy in lipoatrophic HIV-infected patients with dyslipidemia and hypoleptinemia.


METHODS
This was a 6-month, open-label, proof-of-principle pilot study.


METHODS
Metabolic ward studies were performed before and 3 and 6 months after leptin treatment.


METHODS
Participants included eight HIV-infected men with lipoatrophy, fasting triglycerides greater than 300 mg/dl, and serum leptin less than 3 ng/ml.


METHODS
Recombinant human leptin was given by sc injection (0.01 mg/kg and 0.03 mg/kg twice daily for successive 3 month periods).


METHODS
Measures included fat distribution by magnetic resonance imaging and dual-energy X-ray absorptiometry; fasting lipids; insulin sensitivity by euglycemic hyperinsulinemic clamp; endogenous glucose production, gluconeogenesis, glycogenolysis, and whole-body lipolysis by stable isotope tracer studies; oral glucose tolerance testing; liver fat by proton magnetic resonance spectroscopy; and safety.


RESULTS
Visceral fat decreased by 32% (P = 0.001) with no changes in peripheral fat. There were significant decreases in fasting total (15%, P = 0.012), direct low-density lipoprotein (20%, P = 0.002), and non-high-density lipoprotein (19%, P = 0.005) cholesterol. High-density lipoprotein cholesterol increased. Triglycerides, whole-body lipolysis, and free fatty acids decreased during fasting and hyperinsulinemia. Fasting insulin decreased. Endogenous glucose production decreased during fasting and hyperinsulinemia, providing evidence of improved hepatic insulin sensitivity. Leptin was well tolerated but decreased lean mass.


CONCLUSIONS
Leptin treatment was associated with marked improvement in dyslipidemia. Hepatic insulin sensitivity improved and lipolysis decreased. Visceral fat decreased with no exacerbation of peripheral lipoatrophy. Results from this pilot study suggest that leptin warrants further study in patients with HIV-associated lipoatrophy.
Mulligan
Kathleen
K
Department of Medicine, University of California, San Francisco, USA. kathleen.mulligan@ucsf.edu
Khatami
Hootan
H
Schwarz
Jean-Marc
JM
Sakkas
Giorgos K
GK
DePaoli
Alex M
AM
Tai
Viva W
VW
Wen
Michael J
MJ
Lee
Grace A
GA
Grunfeld
Carl
C
Schambelan
Morris
M
D000273:Adipose Tissue / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*; D000328:Adult; D001823:Body Composition / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D015658:HIV Infections / Q000150:complications*; D006801:Humans; D020738:Leptin / Q000172:deficiency / Q000627:therapeutic use*; D008060:Lipodystrophy / Q000188:drug therapy* / Q000209:etiology; D008875:Middle Aged; D010101:Oxygen Consumption / Q000187:drug effects; D011994:Recombinant Proteins / Q000627:therapeutic use; D014280:Triglycerides / Q000097:blood; D014781:Viscera
D020738:Leptin; D011994:Recombinant Proteins; D014280:Triglycerides; D002784:Cholesterol