r-metHuLeptin improves highly active antiretroviral therapy-induced lipoatrophy and the metabolic syndrome, but not through altering circulating IGF and IGF-binding protein levels: observational and interventional studies in humans.
OBJECTIVE
Leptin is an adipocyte secreted hormone and an important regulator of neuroendocrine, metabolic, and immune function. Both r-metHuLeptin and IGF1 administration result in reduced central adipose tissue in subjects with highly active antiretroviral therapy-induced metabolic syndrome (HAART-MS) but whether the effects of leptin are mediated through increasing IGF levels remains unknown.


METHODS
To assess whether r-metHuLeptin improves the HAART-MS by regulating circulating IGF and IGFBPs, we first conducted a cross-sectional study of 118 men and women with HIV infection and >6 months of exposure to antiretroviral medications to examine any association between circulating IGF1 and leptin levels. We also performed a randomized, double-blinded, placebo-controlled, crossover trial of recombinant human leptin (r-metHuLeptin) administration to seven HIV positive men with lipoatrophy and leptin deficiency (leptin <3 ng/ml) related to antiretroviral medication use.


RESULTS
In the observational study, leptin levels were inversely associated with circulating IGF1 levels after adjusting for age and gender (r=0.27 P=0.002), but this inverse association became non-significant after adjustment for % body fat and exercise. In the interventional leptin study, leptin levels increased significantly during r-metHuLeptin treatment (from 1.34+/-0.20 ng/ml at baseline to 17+/-5.05 ng/ml after 8 weeks P=0.046) and metabolic parameters improved including reduced fasting insulin levels and reduced homeostasis model assessment-insulin resistance (HOMA-IR). Despite the increase in circulating leptin levels, there was no change in IGF1, IGF2, free IGF1, or IGF-binding proteins during the 2-month treatment period.


CONCLUSIONS
The effects of r-metHuLeptin in patients with HAART-MS are not mediated through increasing IGF or IGFBP levels.
Brennan
Aoife M
AM
Division of Endocrinology, Diabetes, and Metabolism, Harvard Medical School, Beth Israel Deaconess Medical Center, E/St 816, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.
Lee
Jennifer H
JH
Tsiodras
Sotirios
S
Chan
Jean L
JL
Doweiko
John
J
Chimienti
Sonia N
SN
Wadhwa
Sanjivini G
SG
Karchmer
Adolf W
AW
Mantzoros
Christos S
CS
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects; D000328:Adult; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects; D018592:Cross-Over Studies; D003430:Cross-Sectional Studies; D004359:Drug Therapy, Combination; D005260:Female; D015497:HIV-1; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D020738:Leptin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000172:deficiency; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy* / Q000378:metabolism; D008875:Middle Aged; D010919:Placebos
D018969:Insulin-Like Growth Factor Binding Proteins; D020738:Leptin; D010919:Placebos; C122136:recombinant methionyl human leptin; D007334:Insulin-Like Growth Factor I