Hormone-sensitive Lipase Null Mice Exhibit Signs of Impaired Insulin Sensitivity whereas Insulin Secretion Is Intact

Mulder, Hindrik; Sörhede-Winzell, Maria; Contreras, Juan Antonio; Fex, Malin; Ström, Kristoffer; Ploug, Thorkil; Galbo, H.; Arner, Peter; Lundberg, Cecilia; Sundler, F.; Åhrén, Bo; Holm, Cecilia

doi:10.1074/jbc.m213032200

Cited by 113 publications

(189 citation statements)

References 51 publications

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“…Therefore, it seems likely that the expression of Hsl is higher in ZF islets, which is consistent with the enzyme activity data. The role of HSL in islet beta cell function is unclear, however, as insulin secretion has been shown to be little or not affected in Hsl −/− animals [18,31]. We showed impaired GSIS in only male fasted Hsl −/− mice, and this was completely reversed by the provision of exogenous NEFA [18].…”

Section: Discussionmentioning

confidence: 64%

Beta cell compensation for insulin resistance in Zucker fatty rats: increased lipolysis and fatty acid signalling

et al. 2006

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Aims/hypothesis The aim of this study was to determine the role of fatty acid signalling in islet beta cell compensation for insulin resistance in the Zucker fatty fa/fa (ZF) rat, a genetic model of severe obesity, hyperlipidaemia and insulin resistance that does not develop diabetes. Materials and methods NEFA augmentation of insulin secretion and fatty acid metabolism were studied in isolated islets from ZF and Zucker lean (ZL) control rats. Results Exogenous palmitate markedly potentiated glucosestimulated insulin secretion (GSIS) in ZF islets, allowing robust secretion at physiological glucose levels (5-8 mmol/l).Exogenous palmitate also synergised with glucagon-like peptide-1 and the cyclic AMP-raising agent forskolin to enhance GSIS in ZF islets only. In assessing islet fatty acid metabolism, we found increased glucose-responsive palmitate esterification and lipolysis processes in ZF islets, suggestive of enhanced triglyceride-fatty acid cycling. Interruption of glucose-stimulated lipolysis by the lipase inhibitor Orlistat (tetrahydrolipstatin) blunted palmitate-augmented GSIS in ZF islets. Fatty acid oxidation was also higher at intermediate glucose levels in ZF islets and steatotic triglyceride accumulation was absent. Conclusions/interpretationThe results highlight the potential importance of NEFA and glucoincretin enhancement of insulin secretion in beta cell compensation for insulin resistance. We propose that coordinated glucose-responsive fatty acid esterification and lipolysis processes, suggestive of triglyceride-fatty acid cycling, play a role in the coupling mechanisms of glucose-induced insulin secretion as well as in beta cell compensation and the hypersecretion of insulin in obesity.

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Section: Discussionmentioning

confidence: 64%

Beta cell compensation for insulin resistance in Zucker fatty rats: increased lipolysis and fatty acid signalling

et al. 2006

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“…A tight regulation of hepatic TAG synthesis, hydrolysis and b-oxidation is required to prevent lipid accumulation. HSL was initially observed in adipose tissue, but observations in mice suggest that HSL is also expressed in liver (Mulder et al 2003;Reid et al 2008;Sekiya et al 2008). Hepatic overexpression of HSL (in cells) is shown to reduce hepatic steatosis by promoting b-oxidation, and it has therefore been suggested that HSL may be a therapeutic target for the treatment of fatty liver in human subjects (Reid et al 2008).…”

Section: Discussionmentioning

confidence: 99%

Altered expression of genes involved in lipid metabolism in obese subjects with unfavourable phenotype

et al. 2013

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Obesity (BMI C30 kg/m 2 ) increases the risk of developing lifestyle-related diseases. A subgroup of obese individuals has been described as ''metabolically healthy, but obese'' (MHO). In contrast to at-risk obese (ARO), the MHO phenotype is defined by a favourable lipid profile and a normal or only slightly affected insulin sensitivity, despite the same amount of body fat. The objective was to characterize the metabolic phenotype of MHO subjects. We screened a variety of genes involved in lipid metabolism and inflammation in peripheral blood mononuclear cells (PBMC). Obese subjects (men and women; 18-70 years) with BMI C30 kg/m 2 were characterized as MHO (n = 9) or as ARO (n = 10). In addition, eleven healthy, normal weight subjects characterized as healthy by the same criteria as described for the MHO subjects were included. We found that with similar weight, total fat mass and fat mass distribution, the ARO subjects have increased plasma levels of gamma-glutamyl transpeptidase and free fatty acids. This group also has altered expression levels of a number of genes linked to lipid metabolism in PBMC with reduced gene expression levels of uncoupling protein 2, hormone-sensitive lipase and peroxisome proliferatoractivated receptor d compared with MHO subjects. The present metabolic differences between subgroups of obese subjects may contribute to explain some of the underlying mechanisms causing the increased risk of disease among ARO subjects compared with MHO subjects.

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“…cytes, muscle, liver (27), and islets, 2 as obviated by studies of HSL null mice, whereas the diglyceride lipase activity in tissues of this model is comparatively more retained. Recently, cholesterol has been suggested to play a role in signaling leading to glucose-stimulated insulin secretion (28), opening for speculation that HSL acts, via cholesterol release, to affect insulin secretion.…”

Section: Fig 2 Detection Of Hsl Exon a In Transcripts From Rat Tissmentioning

confidence: 93%

A Novel Hormone-sensitive Lipase Isoform Expressed in Pancreatic β-Cells

Lindvall¹,

Nevsten²,

Ström³

et al. 2004

Journal of Biological Chemistry

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Hormone-sensitive lipase (HSL) is a key enzyme in fatty acid mobilization in many cell types. Two isoforms of HSL are known to date, namely HSL adi (84 kDa in rat) and HSL tes (130 kDa in rat). These are encoded by the same gene, with exons 1-9 encoding the parts that are common to both and an additional 5 -exon encoding the additional amino acids in HSL tes . HSL of various tissues, among these the islet of Langerhans, is larger than HSL adi , but not as large as HSL tes , indicating that there may be other 5 -coding exons. Here we describe the molecular basis for a novel 89-kDa HSL isoform that is expressed in ␤-cells, adipocytes, adrenal glands, and ovaries in the rat and that is encoded by exons 1-9 and exon A, which is spliced to exon 1 and thereby introducing an upstream start codon. The additional 5 -base pairs encode a 43-amino acid peptide, which is highly positively charged. Conglomerates of HSL molecules are in close association with the secretory granules of the ␤-cell, as determined by immunoelectron microscopy with antibodies targeting two separate regions of HSL. We have also determined that the human genomic sequence upstream of exon A has promoter activity in INS-1 cells as well as glucose sensing capability, mediating an increase in expression at high glucose concentration. The minimal promoter is present within 170 bp from the transcriptional start site and maximal glucose responsiveness is conferred by sequence within 850 bp from the transcriptional start site.Because of the established association between type 2 diabetes and obesity, lipids have received much attention in research on the pathophysiology of type 2 diabetes. Lipids are believed to cause insulin resistance in tissues and to alter ␤-cell function. The effect of lipids on ␤-cells has been studied extensively, but the picture that emerges is complex. Different effects are seen depending on parameters such as duration of exposure, concentration, and fatty acid chain length and saturation. Briefly, the presence of free fatty acids is essential for normal glucosestimulated insulin secretion (1, 2) and also has an amplifying action on glucose-stimulated insulin secretion. On the other hand, a prolonged exposure (24 -48 h) to high concentrations (ϳ1 mM) of free fatty acids is detrimental to ␤-cell function and survival (3, 4).In view of this, knowledge of lipid mobilization, lipid storage, and the regulation of these in the ␤-cell are of great interest. Recently, we showed that hormone-sensitive lipase (HSL) 1 is expressed and active in islets of Langerhans and clonal ␤-cells (5). HSL is a key enzyme in fatty acid mobilization in the adipocytes and presumably also in several non-adipocyte cell types (see Ref. 6 for review). It is unique among known lipases in that its activity is acutely controlled by hormones. Catabolic hormones, such as glucagon and catecholamines, activate the enzyme and anabolic hormones (e.g. insulin) decrease its activity. The activity of HSL is principally determined by the intracellular level of cAMP, which con...

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Hormone-sensitive Lipase Null Mice Exhibit Signs of Impaired Insulin Sensitivity whereas Insulin Secretion Is Intact

Cited by 113 publications

References 51 publications

Beta cell compensation for insulin resistance in Zucker fatty rats: increased lipolysis and fatty acid signalling

Beta cell compensation for insulin resistance in Zucker fatty rats: increased lipolysis and fatty acid signalling

Altered expression of genes involved in lipid metabolism in obese subjects with unfavourable phenotype

A Novel Hormone-sensitive Lipase Isoform Expressed in Pancreatic β-Cells

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