Summary Adipose triglyceride lipase (ATGL) is the rate-limiting enzyme for triacylglycerol (TAG) hydrolysis in adipocytes. The precise mechanisms whereby ATGL is regulated remain uncertain. Here we demonstrate that a protein encoded by G0/G1 switch gene 2 (G0S2) is a selective regulator of ATGL. G0S2 is highly expressed in adipose tissue and differentiated adipocytes. When overexpressed in HeLa cells, G0S2 localizes to lipid droplets and prevents their degradation mediated by ATGL. Moreover, G0S2 specifically interacts with ATGL, requiring the hydrophobic domain of G0S2 and the patatin-like domain of ATGL. More importantly, interaction with G0S2 inhibits the TAG hydrolase activity of ATGL. Furthermore, knockdown of endogenous G0S2 accelerates basal and stimulated lipolysis in adipocytes, while overexpression of G0S2 diminishes the rate of lipolysis in both adipocytes and adipose tissue explants. Thus, G0S2 functions to attenuate ATGL action both in vitro and in vivo, underlying a novel mechanism for the regulation of TAG hydrolysis.

In addition to their role in controlling water and salt homeostasis, recent work suggests that aldosterone and mineralocorticoid receptors (MR) may be involved in adipocyte biology. This is of particular relevance given the role of MR as a high-affinity receptor for both mineralocorticoids and glucocorticoids. We have thus examined the effect of aldosterone and MR on white adipose cell differentiation. When cells are cultured in a steroid-free medium, aldosterone promotes acquisition of the adipose phenotype of 3T3-L1 and 3T3-F442A cells in a time-, dose-, and MR-dependent manner. In contrast, late and long-term exposure to dexamethasone inhibits adipocyte terminal maturation. The aldosterone effect on adipose maturation was accompanied by induction of PPARgamma mRNA expression, which was blocked by the MR antagonist spironolactone. Under permissive culture conditions, specific MR down-regulation by siRNAs markedly inhibited 3T3-L1 differentiation by interfering with the transcriptional control of adipogenesis, an effect not mimicked by specific inactivation of the glucocorticoid receptor. These results demonstrate that MR represents an important proadipogenic transcription factor that may mediate both aldosterone and glucocorticoid effects on adipose tissue development. MR thus may be of pathophysiological relevance to the development of obesity and the metabolic syndrome.

The last decade has witnessed tremendous progress in the understanding of the mineralocorticoid receptor (MR), its molecular mechanism of action, and its implications for physiology and pathophysiology. After the initial cloning of MR, and identification of its gene structure and promoters, it now appears as a major actor in protein-protein interaction networks. The role of transcriptional coregulators and the determinants of mineralocorticoid selectivity have been elucidated.Targeted oncogenesis and transgenic mouse models have identified unexpected sites of MR expression and novel roles for MR in non-epithelial tissues. These experimental approaches have contributed to the generation of new cell lines for the characterization of aldosterone signaling pathways, and have also facilitated a better understanding of MR physiology in the heart, vasculature, brain and adipose tissues. This review describes the structure, molecular mechanism of action and transcriptional regulation mediated by MR, emphasizing the most recent developments at the cellular and molecular level. Finally, through insights obtained from mouse models and human disease, its role in physiology and pathophysiology will be reviewed. Future investigations of MR biology should lead to new therapeutic strategies, modulating cell-specific actions in the management of cardiovascular disease, neuroprotection, mineralocorticoid resistance, and metabolic disorders. Received July 20th, 2007; Accepted Novemeber 2nd, 2007; Published Novemeber 30th, 2007 | Abbreviations: 11β-HSD2: 11β-hydroxysteroid dehydrogenase 2; ACE: angiotensin converting enzyme; ACTH: adrenocorticotrophic hormone; ADAMTS1: a disintegrin and metalloproteinase with thrombospondin-like motifs 1; adPHA1: autosomal dominant pseudohypoaldosteronism type 1; AF1: activation function 1; AF2: activation function 2; ANF: atrial natriuretic factor; AR: androgen receptor; ASC2: activating signal cointegrator 2; BMP2: bone morphogenetic protein 2; CBP: CREB binding protein; CHIF: channel-inducing factor; CNS: central nervous system; DAXX: death-associated protein 6; DBD: DNA binding domain; EGF-R: epidermal growth factor receptor; Egr-1: early growth response gene-1; ELL: eleven-nineteen lysine-rich leukemia; ENaC: epithelial sodium channel; ERK: extracellular signal-regulated kinase; ET-1: endothelin-1; FAF1: Fas associated factor 1; FLASH: FLICE associated huge; G6PD: glucose-6-phosphate dehydrogenase; GILZ: glucocorticoid-induced leucine zipper protein; GR: glucocorticoid receptor; GRE: glucocorticoid responsive element; HAS2: hyaluronic acid synthase 2; HDAC: histone deacetylase; hMR: human mineralocorticoid receptor; HRE: hormone responsive element; hsp: heat shock protein; KS-WNK1: kidney specific with no lysine [K] kinase 1; LBD: ligand binding domain; LXRβ: liver X receptor β; MAPK: mitogen-activated protein kinase; MDM2: murine double minute gene 2; MR: mineralocorticoid receptor; MRE: mineralocorticoid responsive element; NAD: nicotinamide adenine dinucleotide; NCoR: nuclear receptor core...

The mineralocorticoid receptor (MR) integrates hormonal signaling and activates the expression of aldosterone target genes, which control various physiological processes. In recent years, evidence has been provided for an important role of MR not only in the regulation of sodium and water homeostasis but also in cardiovascular function, neuronal fate, and adipocyte differentiation. MR belongs to the steroid receptor family that displays common mechanism of action. As a result, some apparent similarities with the glucocorticoid receptor (GR) have shaded MR's own specificities. The description of its gene structure, messenger isoforms, protein variants, functional domains, and posttranslational modifications (phosphorylation, ubiquitinylation, sumoylation, acetylation) as well as a panel of interactions with coregulators, progressively depicted an original portrait of MR and shed light on its specific mechanism of action. In this review, after an overview of MR characteristics, the multiple levels of MR selectivity over other steroid receptors, in particular GR, will be described as well as the consequences for aldosterone-regulated gene expression.

OBJECTIVE-Adipose tissue serves as an integrator of various physiological pathways, energy balance, and glucose homeostasis. Forkhead box-containing protein O subfamily (FoxO) 1 mediates insulin action at the transcriptional level. However, physiological roles of FoxO1 in adipose tissue remain unclear.RESEARCH DESIGN AND METHODS-In the present study, we generated adipose tissue-specific FoxO1 transgenic mice (adipocyte protein 2 [aP 2 ]-FLAG-⌬256) using an aP 2 promoter/ enhancer and a mutant FoxO1 (FLAG⌬256) in which the carboxyl terminal transactivation domain was deleted. Using these mice, we analyzed the effects of the overexpression of FLAG⌬256 on glucose metabolism and energy homeostasis. RESULTS-The aP 2 -FLAG-⌬256 mice showed improved glucose tolerance and insulin sensitivity accompanied with smallersized adipocytes and increased adiponectin (adipoq) and Glut 4 (Slc2a4) and decreased tumor necrosis factor ␣ (Tnf) and chemokine (C-C motif) receptor 2 (Ccr2) gene expression levels in white adipose tissue (WAT) under a high-fat diet. Furthermore, the aP 2 -FLAG-⌬256 mice had increased oxygen consumption accompanied with increased expression of peroxisome proliferator-activated receptor ␥ coactivator (PGC)-1␣ protein and uncoupling protein (UCP)-1 (Ucp1), UCP-2 (Ucp2), and ␤3-AR (Adrb3) in brown adipose tissue (BAT). Overexpression of FLAG⌬256 in T37i cells, which are derived from the hibernoma of SV40 large T antigen transgenic mice, increased expression of PGC-1␣ protein and Ucp1. Furthermore, knockdown of endogenous FoxO1 in T37i cells increased Pgc1␣ (Ppargc1a), Pgc1␤ (Ppargc1b), Ucp1, and Adrb3 gene expression.CONCLUSIONS-These data suggest that FoxO1 modulates energy homeostasis in WAT and BAT through regulation of adipocyte size and adipose tissue-specific gene expression in response to excessive calorie intake. Diabetes 57:563-576, 2008

The presence of mineralocorticoid receptors (MRs) and their physicochemical characteristics were investigated in the heart and blood vessels of rabbits. Immunohistochemical methods using the monoclonal anti-idiotypic antibody H10E, which interacts with the steroid binding domain of MRs, revealed the presence of immunoreactive material in the heart and large blood vessels. In the heart, a positive staining was observed in myocytes and endothelial cells of atria and ventricles. In vessels, MRs were detected in the aorta and pulmonary artery. They were localized in endothelial and vascular smooth muscle cells. No staining was present in the small vascular bed, arterioles, and capillaries. In all these studies, the mineralocorticoid specificity of the staining was assessed by in situ competition experiments with aldosterone and RU486, a glucocorticoid antagonist. The presence of MRs in the heart and vessels was further demonstrated by specific aldosterone binding to one class of high affinity binding sites in the cytosol of the adrenalectomized rabbit heart (Kd, 0.25 nM; maximum MR concentration, 15-20 fmol/mg protein), whose mineralocorticoid specificity has been clearly established by competition studies. Sedimentation gradient analyses revealed that the cardiovascular MR is an 8.5S hetero-oligomer that includes the heat shock protein 90. The physicochemical characteristics of the cardiovascular MRs are virtually identical to those of the renal MRs. Altogether, our results clearly demonstrate the presence of MRs in the cardiovascular system. This supports the possibility of direct aldosterone actions in the heart and blood vessels.

We investigated whether mutations in the gene encoding gonadotropin-releasing hormone 1 (GNRH1) might be responsible for idiopathic hypogonadotropic hypogonadism (IHH) in humans. We identified a homozygous GNRH1 frameshift mutation, an insertion of an adenine at nucleotide position 18 (c.18-19insA), in the sequence encoding the N-terminal region of the signal peptide-containing protein precursor of gonadotropin-releasing hormone (prepro-GnRH) in a teenage brother and sister, who had normosmic IHH. Their unaffected parents and a sibling who was tested were heterozygous. This mutation results in an aberrant peptide lacking the conserved GnRH decapeptide sequence, as shown by the absence of immunoreactive GnRH when expressed in vitro. This isolated autosomal recessive GnRH deficiency, reversed by pulsatile GnRH administration, shows the pivotal role of GnRH in human reproduction.

Besides their growth-promoting properties, GH and IGF-1 regulate a broad spectrum of biological functions in several organs, including the kidney. This review focuses on the renal actions of GH and IGF-1, taking into account major advances in renal physiology and hormone biology made over the last 20 years, allowing us to move our understanding of GH/IGF-1 regulation of renal functions from a cellular to a molecular level. The main purpose of this review was to analyze how GH and IGF-1 regulate renal development, glomerular functions, and tubular handling of sodium, calcium, phosphate, and glucose. Whenever possible, the relative contributions, the nephronic topology, and the underlying molecular mechanisms of GH and IGF-1 actions were addressed. Beyond the physiological aspects of GH/IGF-1 action on the kidney, the review describes the impact of GH excess and deficiency on renal architecture and functions. It reports in particular new insights into the pathophysiological mechanism of body fluid retention and of changes in phospho-calcium metabolism in acromegaly as well as of the reciprocal changes in sodium, calcium, and phosphate homeostasis observed in GH deficiency. The second aim of this review was to analyze how the GH/IGF-1 axis contributes to major renal diseases such as diabetic nephropathy, renal failure, renal carcinoma, and polycystic renal disease. It summarizes the consequences of chronic renal failure and glucocorticoid therapy after renal transplantation on GH secretion and action and questions the interest of GH therapy in these conditions.