Modulation of rat preadipocyte adipose conversion by androgenic status: involvement of C/EBPs transcription factors

Garcı́a, Esther; Lacasa, Michel; Agli, Brigitte; Giudicelli, Yves; Lacasa, Danièle

doi:10.1677/joe.0.1610089

Cited by 31 publications

(19 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There is also evidence in rats that high androgen levels modulate proliferation and differentiation of preadipocytes differentially in specific fat depots (39), and studies in androgen receptor knockout mice suggest the androgens may serve as a negative regulator of adipocyte development (40). Adiponectin levels were decreased in DHT-exposed WT mice, and the s.c. adipocyte size was about twofold increased in all DHT-exposed animals.…”

Section: Discussionmentioning

confidence: 99%

Adiponectin protects against development of metabolic disturbances in a PCOS mouse model

Benrick

Chanclón

Micallef

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

103

View full text Add to dashboard Cite

Adiponectin, together with adipocyte size, is the strongest factor associated with insulin resistance in women with polycystic ovary syndrome (PCOS). This study investigates the causal relationship between adiponectin levels and metabolic and reproductive functions in PCOS. Prepubertal mice overexpressing adiponectin from adipose tissue (APNtg), adiponectin knockouts (APNko), and their wild-type (WT) littermate mice were continuously exposed to placebo or dihydrotestosterone (DHT) to induce PCOS-like traits. As expected, DHT exposure led to reproductive dysfunction, as judged by continuous anestrus, smaller ovaries with a decreased number of corpus luteum, and an increased number of cystic/atretic follicles. A two-way between-groups analysis showed that there was a significant main effect for DHT exposure, but not for genotype, indicating adiponectin does not influence follicle development. Adiponectin had, however, some protective effects on ovarian function. Similar to in many women with PCOS, DHT exposure led to reduced adiponectin levels, larger adipocyte size, and reduced insulin sensitivity in WTs. APNtg mice remained metabolically healthy despite DHT exposure, while APNko-DHT mice were even more insulin resistant than their DHT-exposed littermate WTs. DHT exposure also reduced the mRNA expression of genes involved in metabolic pathways in gonadal adipose tissue of WT and APNko, but this effect of DHT was not observed in APNtg mice. Moreover, APNtg-DHT mice displayed increased pancreatic mRNA levels of insulin receptors, Pdx1 and Igf1R, suggesting adiponectin stimulates beta cell viability/hyperplasia in the context of PCOS. In conclusion, adiponectin improves metabolic health but has only minor effects on reproductive functions in this PCOS-like mouse model. polycystic ovary syndrome | insulin resistance | adipose tissue P olycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder occurring in females (1). PCOS is one of the leading causes of poor fertility and is associated with abdominal obesity, metabolic syndrome, and an increased risk of developing type 2 diabetes (1, 2). Indeed, it has been demonstrated that 30-40% of women with PCOS have impaired glucose tolerance, and as many as 10% develop diabetes by the age of 40 y (3, 4). Despite the negative effect of PCOS on women's health, very little is known about its etiology, including the causal relationship between the reproductive and metabolic features of PCOS. Adipose tissue dysfunction is implicated as a key feature, and both lean and obese women with PCOS have aberrant adipose tissue morphology (5-7). Specifically, we have found that large adipocyte size, low circulating adiponectin levels, and increased waist circumference, but surprisingly, not androgen excess, are factors that are most strongly associated with insulin resistance in women with PCOS (8). Others have shown that hyperandrogenism is associated with intra-abdominal fat deposition (9). Adiponectin is an adipocyte-derived hormone exerting potent positive effec...

show abstract

Section: Discussionmentioning

confidence: 99%

Adiponectin protects against development of metabolic disturbances in a PCOS mouse model

Benrick

Chanclón

Micallef

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

103

View full text Add to dashboard Cite

show abstract

“…C/EBP-␣ is involved in the regulation of liver-specific genes, hepatitis B virus proliferation, and adipogenesis through an androgen-dependent pathway. [52][53][54][55] However, the absence of specific complexes between the RBS and purified C/EBP protein and the lack of a supershift of the complex formed with murine hepatocyte nuclear extract by an anti-C/EBP polyclonal antibody (A.M.D. and A.C.N., unpublished observations, November 15, 2002) suggest that alternative host nuclear proteins are responsible for the androgen-specific binding pattern observed with RBS.…”

Section: Discussionmentioning

confidence: 99%

Sex significantly influences transduction of murine liver by recombinant adeno-associated viral vectors through an androgen-dependent pathway

Davidoff

Zhou

et al. 2003

Blood

201

140

View full text Add to dashboard Cite

A systematic evaluation of the influence of sex on transduction by recombinant adeno-associated viral vector (rAAV) indicated that transgene expression after liver-targeted delivery of vector particles was between 5-to 13-fold higher in male mice compared with female mice, irrespective of the proviral promoter or cDNA and mouse strain. Molecular analysis revealed that the rAAV genome was stably retained in male liver at levels that were 7-fold higher than those observed in females. Further, the sex difference in transduction was observed with AAV-2-and AAV-5-based vectors, which use distinct receptor complexes for infection. In concordance with the differences in AAV transduction, gel shift analysis with nuclear extracts derived from the liver of mice and humans revealed substantially higher binding of host nuclear protein to the rep-binding site (RBS) of AAV inverted terminal repeat (ITR) in males compared with females. Transduction efficiency and binding of nuclear protein to RBS was dramatically reduced in male mice by castration. In contrast, although oophorectomy did not significantly influence rAAV transduction, administration of 5␣ dihydrotestosterone, prior to gene transfer, increased stable hepatocyte gene transfer in females to levels observed in male mice, implying that androgens significantly influence hepatocyte gene transfer. Interestingly, sex did not have a significant effect on AAV gene transfer into nonhepatic tissue, indicating that there are distinct tissue-and sex-specific differences in the mechanisms responsible for efficient transduction with this vector. These results have significant implications for gene therapy of autosomal and acquired disorders affecting the liver. IntroductionRecombinant adeno-associated viral (rAAV) vectors are proving to be highly effective vehicles for the gene therapy of disorders that affect the liver such as hemophilia, ␣1 antitrypsin deficiency, and mucopolysaccharidosis. [1][2][3] The success of these vectors can be ascribed to the fact that they are able to mediate persistent therapeutic expression of transgene such as coagulation factor IX (FIX) in murine and canine models of hemophilia B after portal vein administration of vector particles. [4][5][6][7][8][9][10][11][12] Recently, we have demonstrated sustained expression (Ͼ 18 months) of human FIX (hFIX) at 4% to 10% of physiologic levels in a nonhuman primate model following liver-targeted delivery of AAV vector genomes. 1 Other advantages afforded by AAV vectors include the best safety profile among gene transfer vectors of viral origin as wild-type AAV has never been associated with any human disease. Safety is further enhanced by the dependence of AAV on coinfection with helper virus (usually adeno or herpes virus) for productive infection. Additionally, recombinant vectors are entirely devoid of wild-type viral genes, thus reducing the potential for invoking cell-mediated immune response to foreign viral proteins. 13 These attributes have led to a phase 1 to 2 study to evaluate the safety of rAAV ...

show abstract

“…Brown fat preadipocytes are not present in epididymal cultures, since uncoupling protein 1 is not evident in these cultures after treatment with isoproterenol but is observed in interscapular preadipocyte positive controls (36,41). To induce differentiation, confluent preadipocyte cultures were exposed to a serum-free differentiation-inducing medium (DM) containing 5 g/ml insulin, 10 g/ml transferrin, and 200 pM triiodothyronine in 1:1 DMEM-Ham's F-12 (20). Media were changed every 2 days.…”

Section: Methodsmentioning

confidence: 99%

Increased TNFα and CCAAT/enhancer-binding protein homologous protein with aging predispose preadipocytes to resist adipogenesis

Tchkonia¹,

Pirtskhalava²,

Thomou³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

Fat depot sizes peak in middle age but decrease by advanced old age. This phenomenon is associated with ectopic fat deposition, decreased adipocyte size, impaired differentiation of preadipocytes into fat cells, decreased adipogenic transcription factor expression, and increased fat tissue inflammatory cytokine generation. To define the mechanisms contributing to impaired adipogenesis with aging, we examined the release of TNF␣, which inhibits adipogenesis, and the expression of CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP), which blocks activity of adipogenic C/EBP family members, in preadipocytes cultured from young, middle-aged, and old rats. Medium conditioned by fat tissue, as well as preadipocytes, from old rats impeded lipid accumulation by preadipocytes from young animals. More TNF␣ was released by preadipocytes from old than young rats. Differences in TNF␣-converting enzyme, TNF␣ degradation, or the presence of macrophages in cultures were not responsible. TNF␣ induced rat preadipocyte CHOP expression. CHOP was higher in undifferentiated preadipocytes from old than younger animals. Overexpression of CHOP in young rat preadipocytes inhibited lipid accumulation. TNF␣ short interference RNA reduced CHOP and partially restored lipid accumulation in old rat preadipocytes. CHOP normally increases during late differentiation, potentially modulating the process. This late increase in CHOP was not affected substantially by aging: CHOP was similar in differentiating preadipocytes and fat tissue from old and young animals. Hypoglycemia, which normally causes an adaptive increase in CHOP, was less effective in inducing CHOP in preadipocytes from old than younger animals. Thus increased TNF␣ release by undifferentiated preadipocytes with elevated basal CHOP contributes to impaired adipogenesis with aging.

show abstract

Modulation of rat preadipocyte adipose conversion by androgenic status: involvement of C/EBPs transcription factors

Cited by 31 publications

References 38 publications

Adiponectin protects against development of metabolic disturbances in a PCOS mouse model

Adiponectin protects against development of metabolic disturbances in a PCOS mouse model

Sex significantly influences transduction of murine liver by recombinant adeno-associated viral vectors through an androgen-dependent pathway

Increased TNFα and CCAAT/enhancer-binding protein homologous protein with aging predispose preadipocytes to resist adipogenesis

Contact Info

Product

Resources

About