J Cell Mol Med. 2014 Aug;18(8):1549-61.

Relationship between impaired adipogenesis of retroperitoneal adipose tissue and hypertrophic obesity: role of endogenous glucocorticoid excess.

Zubiría MG, Vidal-Bravo J, Spinedi E, Giovambattista A.

Neuroendocrine Unit, IMBICE (CONICET La Plata-CICPBA), La Plata, Argentina.



Although the pro-adipogenic effect of glucocorticoid (GC) on adipose tissue (AT) precursor cell differentiation is openly accepted, the effect of chronically high peripheral levels of GC on AT mass expansion is not fully understood. In the present study, we aim to assess the in vitro adipogenic capacity of AT precursor cells isolated from retroperitoneal (RP) AT pads of the hypercorticosteronaemic, adult neonatally treated monosodium L-glutamate (MSG) male rat. To ascertain this issue, we explored the in vitro adipogenic process of stromal-vascular fraction (SVF) cells isolated from RPAT pads of 60-day-old MSG rats. The data recorded indicated that RPAT-SVF cells from hypercorticosteronaemic MSG rats, although displaying an enhanced proliferation capacity, differentiated slower than normal cells. This dysfunction was associated with a reduction in key parameters indicative of precursor cell commitment, differentiation capacity and the percentage of fully differentiated adipocytes, with a retarded maturation process. The distorted adipogenic capacity was highly conditioned by RPAT-SVF cells displaying a low committed population and both excessive and reduced expression of anti- (Pref-1 and Wnt-10b) and pro-adipogenic (mineralocorticoid receptor) signals respectively. Notably, the normalization of peripheral corticosterone levels in MSG rats, as a result of bilateral adrenalectomy combined with GC replacement therapy, fully prevented reduced RPAT precursor cell commitment and overall impaired adipogenesis. Our study strongly supports that the impaired adipogenic process observed in the adult hypertrophic obese MSG male rat is a GC-dependent mechanism, thus explaining the unhealthy RPAT expansion observed in human hypertrophic obese phenotypes, such as in the Cushing’s syndrome.

KEYWORDS: ADX; HRT; MSG rat; SVF cells; adipokines; cell lipid; pro-/anti-adipogenic signals; visceral adiposity

PMID: 24913911



Glucocorticoids (GCs) have several effects on adipose tissue (AT) biology; among others, they regulate terminal adipocyte differentiation, AT endocrine function, and lipogenesis-lipolysis balance. Some of these effects are more predominant at the abdominal (AAT) rather than at the subcutaneous (SCAT) AT pad. Cushing’s Syndrome (CS) and the Metabolic Syndrome (MS) human phenotypes share several metabolic abnormalities, such as enhanced peripheral levels of GCs and an increased AAT store, compared with that of SCAT, suggesting that GCs have a pivotal role in the pathogenesis of central obesity.

It is accepted that the ability of AT mass expansion is depending on two processes: the generation of new adipocytes (adipogenesis) and the hypertrophy of mature adipocytes. It has been proposed that at the AT level, hyperplasia mainly contributes to maintain a pool of small and fully functional adipocytes, thus preventing the development of metabolic alterations associated with hypertrophic obesity. In fact, adipocyte hypertrophy is associated with cell dysfunction, i.e. insulin resistance and changes in the pattern of adipokine secretion. During the adipogenic process, adipose precursor cells (APCs) differentiate into mature adipocytes in two sequential steps: commitment of mesenchymal stem cell (MSC) to acquire APC fate, restricting this cell to the adipocyte linage, followed by terminal adipocyte differentiation.

GC is one of the most important inducers for cell differentiation through an inhibitory effect on Wnt10b and Pref-1 genes expression. Several studies addressed that GC can affect adipogenesis through its binding to mineralocorticoid (MR) or/and glucocorticoid (GR) receptor/s, although the contribution of MR and GR in mediating the adipogenic activity of GC has not been fully solved. While the GC-induced adipocyte terminal differentiation has been extensively investigated, conversely, the effect of chronic high GC exposition upon stromal vascular fraction (SVF) cells remains unexplored. The study from Zubiría et al. was focused to understand the in vitro adipogenic capacity of APCs, isolated from AAT pads of chronic hypercorticosteronemic adult male rats. In this research, the effect of a GC rich-endogenous environment elicited a decrease in the adipogenic potential of AAT APCs, despite the potent adipogenic activity of GC. This effect was well correlated with an increased expression of two main anti-adipogenic factors, Pref-1 and Wnt10b. Moreover, reduced expression levels of PPARγ2 and ZFP423 mRNAs, key factors for APCs adipogenic potential, characterized SVFs from hypercorticosteronemic animals. As a result of these findings, it seemed intriguingly to know why the chronic high endogenous levels of GC did not indue any better adipogenic capacity in APCs. With this aim, the expression levels of both steroid receptors were analyzed. Data indicated that the GC-rich environment, although did not alter GR, diminished MR gene expression in APCs. This finding strongly suggests that the development of a MR-mediated, GC-resistant state occurred in hypercorticosteronemic animals. Interestingly, restoring to normal the GC peripheral levels fully corrected AAT dysfunction and its associated metabolic alterations, coincidentally with APCs adipogenic capacity recovery.

It is then concluded that adipogenesis could be inhibited because of long term high GC exposure of APCs, thus contributing to a hypertrophic AAT mass expansion and, as a consequence, to the development of profound endocrine-metabolic dysfunctions that characterize the central obese phenotype. The study strongly highlights the clinical relevance of correcting corticoadrenal hyperactivity to counteract AAT-induced metabolic-endocrine dysfunctions in Cushing’s syndrome and other hypertrophic obese phenotypes.

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