Dysregulation of sterol regulatory element binding protein-1c in livers of morbidly obese women is associated with altered suppressor of cytokine signaling-3 and signal transducer and activator of transcription-1 signaling.

We compared hepatic expression of genes that regulate lipid biosynthesis and metabolic signaling in liver biopsy specimens from women who were undergoing gastric bypass surgery (GBP) for morbid obesity with that in women undergoing ventral hernia repair who had experienced massive weight loss (MWL) after prior GBP. Comprehensive metabolic profiles of morbidly obese (MO) (22 subjects) and MWL (9 subjects) were also compared. Analyses of gene expression in liver biopsies from MO and MWL were accomplished by Affymetrix microarray, real-time polymerase chain reaction, and Western blotting techniques. After GBP, MWL subjects had lost on average 102 lb as compared with MO subjects. This was accompanied by effective reversal of the dyslipidemia and insulin resistance that were present in MO. As compared with MWL, livers of MO subjects exhibited increased expression of sterol regulatory element binding protein (SREBP)-1c and its downstream lipogenic targets, fatty acid synthase and acetyl-coenzyme A-carboxylase-1. Livers of MO subjects also exhibited enhanced expression of suppressor of cytokine signaling-3 protein and attenuated Janus kinase signal transducer and activator of transcription (JAK/STAT) signaling. Consistent with these findings, we found that the human SREBP-1c promoter was positively regulated by insulin and negatively regulated by STAT3. These data support the hypothesis that suppressor of cytokine signaling-3-mediated attenuation of the STAT signaling pathway and resulting enhanced expression of SREBP-1c, a key regulator of de novo lipid biosynthesis, are mechanistically related to the development of hepatic insulin resistance and dyslipidemia in MO women.

Hepatic gene expression in morbidly obese women: implications for disease susceptibility.

The objective of this study was to determine the molecular bases of disordered hepatic function and disease susceptibility in obesity. We compared global gene expression in liver biopsies from morbidly obese (MO) women undergoing gastric bypass (GBP) surgery with that of women undergoing ventral hernia repair who had experienced massive weight loss (MWL) following prior GBP. Metabolic and hormonal profiles were examined in MO vs. MWL groups. Additionally, we analyzed individual profiles of hepatic gene expression in liver biopsy specimens obtained from MO and MWL subjects. All patients underwent preoperative metabolic profiling. RNAs were extracted from wedge biopsies of livers from MO and MWL subjects, and analysis of mRNA expression was carried out using Affymetrix HG-U133A microarray gene chips. Genes exhibiting greater than twofold differential expression between MO and MWL subjects were organized according to gene ontology and hierarchical clustering, and expression of key genes exhibiting differential regulation was quantified by real-time-polymerase chain reaction (RT-PCR). We discovered 154 genes to be differentially expressed in livers of MWL and MO subjects. A total of 28 candidate disease susceptibility genes were identified that encoded proteins regulating lipid and energy homeostasis (PLIN, ENO3, ELOVL2, APOF, LEPR, IGFBP1, DDIT4), signal transduction (MAP2K6, SOCS-2), postinflammatory tissue repair (HLA-DQB1, SPP1, P4HA1, LUM), bile acid transport (SULT2A, ABCB11), and metabolism of xenobiotics (GSTT2, CYP1A1). Using gene expression profiling, we have identified novel candidate disease susceptibility genes whose expression is altered in livers of MO subjects. The significance of altered expression of these genes to obesity-related disease is discussed.

Regulation of leptin release by insulin, glucocorticoids, G(i)-coupled receptor agonists, and pertussis toxin in adipocytes and adipose tissue explants from obese humans in primary culture.

The basal release of leptin by adipocytes from massively obese human subjects incubated for 48 hours in serum-free suspension culture was comparable to that by explants of subcutaneous adipose tissue from the same obese individuals. There was no stimulation due to dexamethasone or insulin alone of leptin release by adipocytes. However, the combination of insulin and dexamethasone doubled leptin release by adipocytes. The release of leptin was also stimulated by agonists of G(i)-coupled receptors (prostaglandin E(2) [PGE(2)], brimonidine [an alpha(2) catecholamine agonist] and cyclopentyladenosine [CPA]) in the presence of dexamethasone. Leptin release by these agents was further enhanced by insulin in both adipocytes and adipose tissue. Pertussis toxin, which irreversibly inactivates G(i) heterotrimers, inhibited leptin release and abolished the stimulatory effects of G(i)-coupled receptor agonists. However, pertussis toxin did not block the stimulation of leptin release by insulin in either adipose tissue or adipocytes. These data indicate that the release of leptin by human adipocytes cultured for 48 hours in a serum-free medium is comparable to that by explants of adipose tissue except that dexamethasone stimulation of leptin release requires the presence of insulin.