Adipose Tissue is a Potential Source of Hyperandrogenism in Obese Female Rats

ObjectiveObesity in females is often associated with metabolic complications and hyperandrogenism, but the sources of androgens are not completely understood. Therefore, this study investigated whether adipose tissue could be a source of androgens promoting hyperandrogenism development in obese female rats. MethodsGene expression of steroidogenic enzymes and testosterone levels were determined in periovarian and inguinal adipose tissue and in the supernatant of cultured preadipocytes and adipocytes. The conversion of pregnenolone to androgens was analyzed by thin-layer chromatography. ResultsSubstantial amounts of testosterone in adipose tissue (25-153 ng/g tissue) and in the supernatant of adipocytes (0.33-0.69 ng/ten thousand cells]) were found. StAR and steroidogenic enzymes encoded by genes including Cyp11A1, Cyp17A1, Cyp19, Hsd3b2, Hsd17b3, and Srd5a2 were expressed in adipose tissue and cultured cells. Thin layer chromatography data revealed that preadipocytes and adipocytes were able to convert pregnenolone to testosterone. Higher levels for all steroidogenic enzymes were found in both depots of obese animals compared with lean animals, with significantly higher levels in inguinal tissue. ConclusionsThe whole steroidogenic machinery and capacity for testosterone biosynthesis were found in fat depots of female rats. These findings support the hypothesis that adipose tissue may contribute substantially to the hyperandrogenism in female obesity

A novel compound heterozygous leptin receptor mutation causes more severe obesity than in Lepr(db/db) mice

The leptin receptor (Lepr) pathway is important for food intake regulation, energy expen-diture, and body weight. Mutations in leptin and the Lepr have been shown to cause early-onset severe obesity in mice and humans. In studies with C57BL/ 6NCrl mice, we found a mouse with extreme obesity. To identify a putative spontaneous new form of monogenic obesity, we performed backcross studies with this mouse followed by a quantitative trait locus (QTL) analysis and sequencing of the selected chro-mosomal QTL region. We thereby identified a novel Lepr mutation (C57BL/6N-Lepr(L536Hfs*6-1NKB)), which is located at chromosome 4, exon 11 within the CRH2-leptin-binding site. Compared with C57BL/6N mice, Lepr(L536Hfs*6) develop early onset obesity and their body weight exceeds that of Leprdb/db mice at an age of 30 weeks. Similar to Leprdb/db mice, the Lepr(L536Hfs*6) model is characterized by hyperphagia, obesity, lower energy expenditure and activity, hyperglycemia, and hyperinsulinemia compared with C57BL/6N mice. Crossing Leprdb/wt with Lepr(L536Hfs*6/wt) mice results in compound heterozygous Lepr(L536Hfs*6/db) mice, which develop even higher body weight and fat mass than both homozygous Lepr(db/db) and Lepr(L536Hfs*6) mice. Compound heterozygous Lepr deficiency affecting functionally different regions of the Lepr causes more severe obesity than the parental homozygous mutations.Peer reviewe

Leptin restores markers of female fertility in lipodystrophy

Objectives: Female reproductive dysfunction occurs in patients with pathological loss of adipose tissue, i.e. lipodystrophy (LD). However, mechanisms remain largely unclear and treatment effects of adipocyte-derived leptin have not been assessed in LD animals. Methods: In the current study, C57131/6 LD mice on a low-density lipoprotein receptor knockout background were treated with leptin or saline for 8 weeks and compared to non-LD controls. Results: The number of pups born was 37% lower in breeding pairs consisting of LD female mice x non-LD male mice (n = 3.3) compared to LD male mice x non-LD female mice (n = 5.2) (p < 0.05). Mean uterus weight was significantly lower in the saline-treated LD group (18.8 mg) compared to non-LD controls (52.9 mg; p < 0.0001) and increased significantly upon leptin treatment (46.5 mg; p < 0.001). The mean number of corpora lutea per ovary was significantly lower in saline-treated LD animals compared to non-LD controls (p < 0.01) and was restored to non-LD control levels by leptin (p < 0.05). Mechanistically, mRNA expression of ovarian follicle stimulating hormone receptor (p < 0.01) and estrogen receptor beta (p < 0.05), as well as of pituitary luteinizing hormone beta subunit (p < 0.001) and follicle-stimulating hormone beta subunit (p < 0.05), was significantly up regulated in LD mice compared to non-LD controls. In addition, mean time to vaginal opening as a marker of puberty onset was delayed by 12.5 days in LD mice (50.9 days) compared to non-LD controls (38.4 days; p < 0.001). Conclusions: Female LD animals show impaired fertility which is restored by leptin. Future studies should assess leptin as a subfertility treatment in human leptin-deficiency disorders

Genetic dissection of serum vaspin highlights its causal role in lipid metabolism

Peer reviewe