Adipocyte Lipases and Defect of Lipolysis in Human Obesity

Department of Chemistry, Washington University in St. Louis, San Luis, Missouri, United States
Diabetes (Impact Factor: 8.1). 12/2005; 54(11):3190-7. DOI: 10.2337/diabetes.54.11.3190
Source: PubMed


The mobilization of fat stored in adipose tissue is mediated by hormone-sensitive lipase (HSL) and the recently characterized adipose triglyceride lipase (ATGL), yet their relative importance in lipolysis is unknown. We show that a novel potent inhibitor of HSL does not inhibit other lipases. The compound counteracted catecholamine-stimulated lipolysis in mouse adipocytes and had no effect on residual triglyceride hydrolysis and lipolysis in HSL-null mice. In human adipocytes, catecholamine- and natriuretic peptide-induced lipolysis were completely blunted by the HSL inhibitor. When fat cells were not stimulated, glycerol but not fatty acid release was inhibited. HSL and ATGL mRNA levels increased concomitantly during adipocyte differentiation. Abundance of the two transcripts in human adipose tissue was highly correlated in habitual dietary conditions and during a hypocaloric diet, suggesting common regulatory mechanisms for the two genes. Comparison of obese and nonobese subjects showed that obesity was associated with a decrease in catecholamine-induced lipolysis and HSL expression in mature fat cells and in differentiated preadipocytes. In conclusion, HSL is the major lipase for catecholamine- and natriuretic peptide-stimulated lipolysis, whereas ATGL mediates the hydrolysis of triglycerides during basal lipolysis. Decreased catecholamine-induced lipolysis and low HSL expression constitute a possibly primary defect in obesity.

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    • "FFA were measured by an enzymatic assay (NEFA C, Wako Chemicals GmbH, Japan). Glycerol was measured by a spectrophotometric method [23]. All other determinations were carried out by standard automated procedures. "
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    ABSTRACT: Ephedrine/caffeine combination (EC) has been shown to induce a small-to-moderate weight loss in obese patients. Several mechanisms have been proposed, among which an increased thermogenic capacity of skeletal muscle consequent to the EC-induced up-regulation of uncoupling protein 3 (UCP3) gene expression. We did a parallel group double-blind, placebo-controlled, 4-week trial to investigate this hypothesis. Thirteen morbidly obese women (25–52 years of age, body-mass index 48.0±4.0 kg/m2, range 41.1–57.6) were randomly assigned to EC (200/20 mg, n = 6) or to placebo (n = 7) administered three times a day orally, before undergoing bariatric surgery. All individuals had an energy-deficit diet equal to about 70% of resting metabolic rate (RMR) diet (mean 5769±1105 kJ/day). The RMR analysed by intention to treat and the UCP3 (long and short isoform) mRNA levels in rectus abdominis were the primary outcomes. Body weight, plasma levels of adrenaline, noradrenaline, triglycerides, free fatty acids, glycerol, TSH, fT4, and fT3 were assessed, as well as fasting glucose, insulin and HOMA index, at baseline and at the end of treatments. Body weight loss was evident in both groups when compared to baseline values (overall −5.2±3.2%, p<0.0001) without significant differences between the treated groups. EC treatment increased the RMR (+9.2±6.8%, p = 0.020), differently from placebo which was linked to a reduction of RMR (−7.6±6.5%, p = 0.029). No significant differences were seen in other metabolic parameters. Notably, no changes of either UCP3 short or UCP3 long isoform mRNA levels were evident between EC and placebo group. Our study provides evidence that 4-week EC administration resulted in a pronounced thermogenic effect not related to muscle UCP3 gene expression and weight loss in morbidly obese females under controlled conditions. Trial Registration NCT02048215
    PLoS ONE 06/2014; 9(6):e98244. DOI:10.1371/journal.pone.0098244 · 3.23 Impact Factor
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    • "Expansion of AT occurs through hyperplasia or hypertrophy that is in adult obesity prevailing. Hypertrophy of adipocytes is connected with their dysfunction manifested by lower insulin sensitivity, higher basal lipolysis and altered production of cytokines contributing to a development of chronic low-grade inflammation [1,2]. Even though the exact molecular insult leading to such adipocyte dysfunction is not clear, it appears that the nutrient overload creating excessive demands on the endoplasmic reticulum (ER) could be an important if not central contributor [3,4]. "
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    ABSTRACT: Stress of endoplasmic reticulum (ERS) is one of the molecular triggers of adipocyte dysfunction and chronic low inflammation accompanying obesity. ERS can be alleviated by chemical chaperones from the family of bile acids (BAs). Thus, two BAs currently used to treat cholestasis, ursodeoxycholic and tauroursodeoxycholic acid (UDCA and TUDCA), could potentially lessen adverse metabolic effects of obesity. Nevertheless, BAs effects on human adipose cells are mostly unknown. They could regulate gene expression through pathways different from their chaperone function, namely through activation of farnesoid X receptor (FXR) and TGR5, G-coupled receptor. Therefore, this study aimed to analyze effects of UDCA and TUDCA on human preadipocytes and differentiated adipocytes derived from paired samples of two distinct subcutaneous adipose tissue depots, abdominal and gluteal. While TUDCA did not alter proliferation of cells from either depot, UDCA exerted strong anti-proliferative effect. In differentiated adipocytes, acute exposition to neither TUDCA nor UDCA was able to reduce effect of ERS stressor tunicamycin. However, exposure of cells to UDCA during whole differentiation process decreased expression of ERS markers. At the same time however, UDCA profoundly inhibited adipogenic conversion of cells. UDCA abolished expression of PPARγ and lipogenic enzymes already in the early phases of adipogenesis. This anti-adipogenic effect of UDCA was not dependent on FXR or TGR5 activation, but could be related to ability of UDCA to sustain the activation of ERK1/2 previously linked with PPARγ inactivation. Finally, neither BAs did lower expression of chemokines inducible by TLR4 pathway, when UDCA enhanced their expression in gluteal adipocytes. Therefore while TUDCA has neutral effect on human preadipocytes and adipocytes, the therapeutic use of UDCA different from treating cholestatic diseases should be considered with caution because UDCA alters functions of human adipose cells.
    PLoS ONE 12/2013; 8(12):e82086. DOI:10.1371/journal.pone.0082086 · 3.23 Impact Factor
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    • "The phenotype of the ATKO mice now points toward the possibility that indeed intrinsic deficiency in efficient FFA mobilization in WAT may be sufficient to cause systemic metabolic dysfunction , maybe as a consequence of impaired WAT metabolic flexibility upon an imbalanced equilibrium between lipid storage and mobilization (Galgani et al., 2008), and/or the simultaneous dysregulation of inflammatory and adipocytokine pathways as observed upon TBLR1 deficiency. Indeed, the TBLR1 knockout phenocopies the inhibition of lipolysis and of HSL and ATGL expression as generally observed in obese human patients (Jocken et al., 2007; Langin et al., 2005; Large et al., 1999) and strongly resembles the metabolic dysfunction in woman with polycystic ovary syndrome (PCOS), including adipocyte hypertrophy, attenuated lipolytic response to catecholamine exposure, obesity, adipose tissue inflammation, and insulin resistance (Villa and Pratley, 2011). "
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    ABSTRACT: Lipid mobilization (lipolysis) in white adipose tissue (WAT) critically controls lipid turnover and adiposity in humans. While the acute regulation of lipolysis has been studied in detail, the transcriptional determinants of WAT lipolytic activity remain still largely unexplored. Here we show that the genetic inactivation of transcriptional cofactor transducin beta-like-related 1(TBLR1) blunts the lipolytic response of white adipocytes through the impairment of cAMP-dependent signal transduction. Indeed, mice lacking TBLR1 in adipocytes are defective in fasting-induced lipid mobilization and, when placed on a high-fat-diet, show aggravated adiposity, glucose intolerance, and insulin resistance. TBLR1 levels are found to increase under lipolytic conditions in WAT of both human patients and mice, correlating with serum free fatty acids (FFAs). As a critical regulator of WAT cAMP signaling and lipid mobilization, proper activity of TBLR1 in adipocytes might thus represent a critical molecular checkpoint for the prevention of metabolic dysfunction in subjects with obesity-related disorders.
    Cell metabolism 03/2013; 17(4). DOI:10.1016/j.cmet.2013.02.010 · 17.57 Impact Factor
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