Expanded adipose tissue mass increases the risk for many clinical conditions including diabetes, hypertension, coronary atherosclerotic heart disease, and some forms of cancer. Therefore, it is imperative that we understand the mechanisms by which fat pads expand. The enlargement of fat cells during the development of obesity has been previously hypothesized to be a triggering factor for the proliferation of new fat cells. There is now a preponderance of evidence that adipose tissue is a source of growth factors such as IGF-I, IGF binding proteins, TNF alpha, angiotensin II, and MCSF that are capable of stimulating proliferation. The relative importance of these autocrine/paracrine factors in the normal control of preadipocyte proliferation is unknown. In addition, the proliferative response of preadipocytes to the paracrine milieu is undoubtedly modulated by neural inputs to fat tissue and/or serum factors. Together, these multiple regulatory controls orchestrate overall and region-specific adipose tissue cellularity responses associated with the development of hyperplastic obesity. Both in vivo and in vitro studies are needed to understand the complex, interacting physiological mechanisms by which growth of this important organ is regulated.

The biology of white adipocyte proliferation.

Testosterone supplementation in men decreases fat mass; however, the mechanisms by which it inhibits fat mass are unknown. We hypothesized that testosterone inhibits adipogenic differentiation of preadipocytes by activation of androgen receptor (AR)/beta-catenin interaction and subsequent translocation of this complex to the nucleus thereby bypassing canonical Wnt signaling. We tested this hypothesis in 3T3-L1 cells that differentiate to form fat cells in adipogenic medium. We found that these cells express AR and that testosterone and dihydrotestosterone dose-dependently inhibited adipogenic differentiation as analyzed by Oil Red O staining and down-regulation of CCAAT/enhancer binding protein-alpha and -delta and peroxisome proliferator-activated receptor-gamma2 protein and mRNA. These inhibitory effects of androgens were partially blocked by flutamide or bicalutamide. Androgen treatment was associated with nuclear translocation of beta-catenin and AR. Immunoprecipitation studies demonstrated association of beta-catenin with AR and T-cell factor 4 (TCF4) in the presence of androgens. Transfection of TCF4 cDNA inhibited adipogenic differentiation, whereas a dominant negative TCF4 cDNA construct induced adipogenesis and blocked testosterone's inhibitory effects. Our gene array analysis indicates that testosterone treatment led to activation of some Wnt target genes. Expression of constitutively activated AR fused with VP-16 did not inhibit the expression of CCAAT/enhancer binding protein-alpha in the absence of androgens. Testosterone and dihydrotestosterone inhibit adipocyte differentiation in vitro through an AR-mediated nuclear translocation of beta-catenin and activation of downstream Wnt signaling. These data provide evidence for a regulatory role for androgens in inhibiting adipogenic differentiation and a mechanistic explanation consistent with the observed reduction in fat mass in men treated with androgens.

Testosterone Inhibits Adipogenic Differentiation in 3T3-L1 Cells: Nuclear Translocation of Androgen Receptor Complex with β-Catenin and T-Cell Factor 4 May Bypass Canonical Wnt Signaling to Down-Regulate Adipogenic Transcription Factors

Androgens and body fat distribution.

The quest for effective strategies to treat obesity has propelled fat research into an exploration of the molecular processes that drive adipocyte formation, and hence body fat mass. The development of obesity is dependent on the coordinated interplay of adipocyte hypertrophy (increased fat cell size), adipocyte hyperplasia (increased fat cell number), and angiogenesis. Evidence suggests that adipocyte hyperplasia, or adipogenesis, occurs throughout life, both in response to normal cell turnover as well as in response to the need for additional fat mass stores that arises when caloric intake exceeds nutritional requirements. Adipogenesis involves two major events-the recruitment and proliferation of adipocyte precursor cells, called preadipocytes, followed by the subsequent conversion of preadipocytes, or differentiation, into mature fat cells. In vitro studies using experimental and primary preadipocyte cell lines have uncovered the mechanisms that drive the adipogenic process, a tightly controlled sequence of events guided by the strict temporal regulation of multiple inhibitory and stimulatory signaling events involving regulators of cell-cycle functions and differentiation factors. This article reviews the current understanding of adipogenesis with emphasis on the various stages of adipocyte development; on key hormonal, nutritional, paracrine, and neuronal control signals; as well as on the components involved in cell-cell or cell-matrix interactions that are pivotal in regulating fat cell formation. Special consideration is given to clinical applications derived from adipogenesis research with impact on medical, surgical and cosmetic fields.

Subcutaneous fat in normal and diseased states 3. Adipogenesis: from stem cell to fat cell.

https://www.europeanurology.com/article/S0302-2838(07)00235-7/pdf/testosterone-and-erectile-function-from-basic-research-to-a-new-clinical-paradigm-for-managing-men-with-androgen-insufficiency-and-erectile-dysfunction

Testosterone and erectile function: from basic research to a new clinical paradigm for managing men with androgen insufficiency and erectile dysfunction.

Androgenic status affects rat preadipocyte adipose conversion from two deep intra-abdominal (epididymal and perirenal) fat depots differently. The aim of this study was to establish whether these site-specific alterations of adipogenesis are related to altered expressions of the transcriptional factors regulating proliferation and differentiation of preadipocytes, c-myc and CCAAT/enhancer binding proteins (C/EBPs: C/EBPalpha and beta). The increased proliferation of epididymal and perirenal preadipocytes from castrated rats was not linked to variations in c-myc mRNA and protein levels. The expression of the early marker of adipogenesis, lipoprotein lipase (LPL), was decreased by androgenic deprivation in epididymal cells but remained insensitive to the androgenic status in perirenal preadipocytes. In contrast, LPL expression increased in subcutaneous preadipocytes from castrated rats, an effect which was partly corrected by testosterone treatment. Expression of C/EBPbeta was unaffected by androgenic status whatever the anatomical origin of the preadipocytes. In contrast, the mRNA and protein levels of C/EBPalpha were greatly decreased by androgenic deprivation in epididymal cells, an alteration which could not be corrected by in vivo testosterone administration. Altogether these results demonstrated that in preadipocytes androgenic deprivation affects site-specifically the expression of LPL, an early marker of adipogenesis and of C/EBPalpha, a master regulator of adipogenesis. These observations contribute to an explanation of why castration induces defective adipose conversion in rat epididymal preadipocytes specifically.

/pdf/modulation-of-rat-preadipocyte-adipose-conversion-by-3ocv6k9fhk.pdf

M Lacasa

Papers

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