Adipose tissue gene expression in patients with a loss of function mutation in the leptin receptor.
BACKGROUND
In order to maintain body weight regulation, leptin directly or indirectly signals nutritional changes to key organs, but little is known about its target genes in human adipose tissue. Leptin receptor loss of function is a unique way to explore the role of leptin in the regulation of adipose tissue.


OBJECTIVE
We studied the consequences of the absence of leptin signaling on adipocyte gene expression in two girls with a mutation in the leptin receptor. The expression levels of the ob gene and adipocyte transcription factors (SREBP1c, C/EPBalpha, beta, PPARgamma1, gamma2) were quantified by RT-PCR in subcutaneous adipose tissue of these patients and of 10 morbidly obese women.


RESULTS
Ob mRNA levels in subjects lacking the leptin receptor were not overexpressed but were in the range that could be expected from their BMI (58 and 26 amol/ micro g total mRNA, range in obese women: 26-69). Expression of the five transcription factors was also in the same range in the affected patients and in morbidly obese women (7.7 and 6.8 amol/ micro g total mRNA, range: 2.2-9.4 for SREBP1c, 159 and 51 range: 51-406 for C/EPBalpha, 6.1 and 3.3 range: 2.4-24.8 for C/EPBbeta, 16.7 and 27.4 range: 9.4-29.7 for PPARgamma1 and 1.7 and 5.4 amol/ micro g total mRNA range: 1.7-8.8 for PPARgamma2). Significant correlation was found between the mRNA levels of leptin and PPARgamma2 and leptin and C/EBPalpha whereas no correlation was observed between leptin and SREBP1c, PPARgamma1, or C/EBPbeta mRNA levels.


CONCLUSIONS
In patients lacking leptin signaling, the fact that ob gene expression is adequately adapted to their body fat mass argues against a direct negative feedback loop in the regulation of leptin expression in humans. The normal expression of several transcription factors, known to be dependent of the nutritional status, suggests that leptin is not a major contributor of their in vivo transcriptional regulation in human adipose tissue.
Clément
K
K
Equipe d'Accueil 3502 Université Paris VI et Service de Nutrition, Hôtel-Dieu, Formation Associée Claude Bernard, France. karine.clement@htd.ap-hop-paris.fr
Vega
N
N
Laville
M
M
Pelloux
V
V
Guy-Grand
B
B
Basdevant
A
A
Vidal
H
H
D017667:Adipocytes / Q000502:physiology*; D000328:Adult; D000368:Aged; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009767:Obesity, Morbid / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D054411:Receptors, Leptin; D017423:Sequence Analysis, RNA; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors / Q000235:genetics
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; C515448:LEPR protein, human; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D054411:Receptors, Leptin; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors