Elevated stearoyl-CoA desaturase-1 expression in skeletal muscle contributes to abnormal fatty acid partitioning in obese humans

Hulver, Matthew W.; Berggren, Jason R.; Carper, Michael J.; Miyazaki, Masaru; Ntambi, James M.; Hoffman, Eric P.; Thyfault, John P.; Stevens, Robert; Dohm, G. Lynis; Houmard, Joseph A.; Muoio, Deborah M.

doi:10.1016/j.cmet.2005.09.002

Cited by 331 publications

(336 citation statements)

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“…This suggests that anthropometric variables of obesity, which largely relate to adipose tissue mass, are a strong indicator of adipose tissue lipid overspill into skeletal muscle. This is in accordance with another study showing that IMCL content in myotubes from lean control and obese non-diabetic participants was significantly related to BMI of the donor [5]. However, we and others [10] have shown that type 2 diabetes alone, in the absence of whole-body indicators of obesity, is also associated with skeletal muscle lipid accumulation.…”

Section: Discussionsupporting

confidence: 93%

“…The study of IMCL accumulation in humans is limited by the small amount of material available. Primary human myotubes isolated from patients suffering from type 2 diabetes have been shown to retain and display the majority of the defects previously observed ex vivo [5][6][7]. This in vitro muscle system provides an attractive model, in which lipid accumulation can be evaluated independently of the systemic influences of the in vivo environment.…”

Section: Introductionmentioning

confidence: 92%

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Intramyocellular lipid accumulation is associated with permanent relocation ex vivo and in vitro of fatty acid translocase (FAT)/CD36 in obese patients

et al. 2010

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Aims/hypothesis Intramyocellular lipids (IMCL) accumulation is a classical feature of metabolic diseases. We hypothesised that IMCL accumulate mainly as a consequence of increased adiposity and independently of type 2 diabetes. To test this, we examined IMCL accumulation in two different models and four different populations of participants: muscle biopsies and primary human muscle cells derived from non-obese and obese participants with or without type 2 diabetes. The mechanism regulating IMCL accumulation was also studied. Methods Muscle biopsies were obtained from ten non-obese and seven obese participants without type 2 diabetes, and from eight non-obese and eight obese type 2 diabetic patients. Mitochondrial respiration, citrate synthase activity and both ON, Canada Diabetologia (2010) 53:1151-1163 DOI 10.1007/s00125-010-1708 accumulation is dependent upon obesity or type 2 diabetes and is related to sarcolemmal FAT/CD36 relocation. In cultured myotubes, IMCL content and FAT/CD36 relocation are independent of type 2 diabetes, suggesting that distinct factors in obesity and type 2 diabetes contribute to permanent FAT/CD36 relocation ex vivo.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 92%

Intramyocellular lipid accumulation is associated with permanent relocation ex vivo and in vitro of fatty acid translocase (FAT)/CD36 in obese patients

et al. 2010

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“…Considering these important observations, we hypothesize that skeletal muscle insulin resistance induces myostatin expression in response to a cellular state of starvation. Or put another way, the metabolic milieu of obese skeletal muscle may be similar to that of starving muscle because of the insulin-resistant state in which glucose uptake is severely constrained and the oxidative catabolism of lipid is reduced or incomplete; however, this hypothesis has not been tested (10,13,14,38). It has also been shown that myostatin expression in muscle is reduced acutely with endurance and resistance exercise (39).…”

Section: Discussionmentioning

confidence: 99%

“…Primary human muscle cells derived from three lean and extremely obese (based on BMI) subjects were grown in medium with (obese samples) or without (lean samples) 13 C-Lys, and then secreted proteins were collected and analyzed. The harvesting and culturing of satellite cells from skeletal muscle biopsy material were conducted as previously described (10,12). For metabolic labeling for quantitative proteomic profiling, cells were incubated in Dulbecco's modified Eagle's medium (DMEM), which was custom made without lysine (Invitrogen, Carlsbad, CA).…”

Section: Methodsmentioning

confidence: 99%

Increased Secretion and Expression of Myostatin in Skeletal Muscle From Extremely Obese Women

et al. 2009

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OBJECTIVE-Obesity is associated with endocrine abnormalities that predict the progression of insulin resistance to type 2 diabetes. Because skeletal muscle has been shown to secrete proteins that could be used as biomarkers, we characterized the secreted protein profile of muscle cells derived from extremely obese (BMI 48.8 Ϯ 14.8 kg/m 2 ; homeostasis model assessment [HOMA] 3.6 Ϯ 1.0) relative to lean healthy subjects (BMI 25.7 Ϯ 3.2 kg/m 2 ; HOMA 0.8 Ϯ 0.2).RESEARCH DESIGN AND METHODS-We hypothesized that skeletal muscle would secrete proteins that predict the severity of obesity. To test this hypothesis, we used a "bottom-up" experimental design using stable isotope labeling by amino acids in culture (SILAC) and liquid chromatography/mass spectometry/ mass spectometry (LC-MS/MS) to both identify and quantify proteins secreted from cultured myotubes derived from extremely obese compared with healthy nonobese women.RESULTS-Using SILAC, we discovered a 2.9-fold increase in the secretion of myostatin from extremely obese human myotubes. The increased secretion and biological activity of myostatin were validated by immunoblot (3.16 Ϯ 0.18, P Ͻ 0.01) and a myoblast proliferation assay using conditioned growth medium. Myostatin was subsequently shown to increase in skeletal muscle (23%, P Ͻ 0.05) and plasma (35%, P Ͻ 0.05) and to correlate (r 2 ϭ 0.6, P Ͻ 0.05) with the severity of insulin resistance.CONCLUSIONS-Myostatin is a potent antianabolic regulator of muscle mass that may also play a role in energy metabolism. These findings show that increased expression of myostatin in skeletal muscle with obesity and insulin resistance results in elevated circulating myostatin. This may contribute to systemic metabolic deterioration of skeletal muscle with the progression of insulin resistance to type 2 diabetes. Diabetes 58: [30][31][32][33][34][35][36][37][38] 2009 O besity and type 2 diabetes are associated with endocrine abnormalities that are either precipitated by or precede the onset of peripheral insulin resistance (1). These include changes in circulating proteins and peptides that produce endothelial dysfunction, low-grade inflammation, and a prothrombotic state, all of which contribute to increased cardiovascular risk (2-4). Secreted proteins or the "secretome" constitute an important class of biologically active molecules that are released into circulation where they facilitate cross-talk between organ systems. Because secreted proteins are also involved in the progression of cardiovascular disease and cancer, there is significant interest in mining the secretome for novel biological markers (5). Whereas endocrine organs specialize in the secretion of proteins into circulation, there is mounting evidence that adipose tissue and skeletal muscle constitutively or intermittently secrete bioactive proteins (6,7). In this study, we hypothesized that skeletal muscle of extremely obese and insulinresistant women would secrete proteins into circulation that act as prognostic or diagnostic biomarkers of obesityass...

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“…25 Whatever the explanation, however, our studies investigating SCD1 gene regulation under physiological settings of adaptive changes in thermogenesis in response to diet or to cold argue against a primary role for SCD1 in the effector mechanisms by which the sympathoadrenal system regulates adaptive thermogenesis. Whether, from a therapeutic standpoint, approaches that target both SCD1 and molecular effectors of thermogenesis under b-adrenergic control might be more effective than targeting SCD1 alone are potential avenues for future research in obesity management.…”

mentioning

confidence: 87%

β-Adrenergic control of stearoyl-CoA desaturase 1 repression in relation to sympathoadrenal regulation of thermogenesis

Mainieri

Montani

Seydoux³

et al. 2006

Int J Obes

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Mice lacking b-adrenoceptors, which mediate the thermogenic effects of norepinephrine and epinephrine, show diminished thermogenesis and high susceptibility to obesity, whereas mice lacking stearoyl-CoA desaturase 1 (SCD1), which catalyzes the synthesis of monounsaturated fatty acids, show enhanced thermogenesis and high resistance to obesity. In testing whether b-adrenergic control of thermogenesis might be mediated via repression of the SCD1 gene, we found that in mice lacking b-adrenoceptors, the gene expression of SCD1 is elevated in liver, skeletal muscle and white adipose tissue. In none of these tissues/organs, however, could a link be found between increased sympathetic nervous system activity and diminished SCD1 gene expression when thermogenesis is increased in response to diet or cold, nor is the SCD1 transcript repressed by the administration of epinephrine. Taken together, these studies suggest that the elevated SCD1 transcript in tissues of mice lacking b-adrenoceptors is not a direct effect of blunted b-adrenergic signalling, and that b-adrenergic control of SCD1 repression is unlikely to be a primary effector mechanism in sympathoadrenal regulation of thermogenesis. Whether approaches that target both SCD1 and molecular effectors of thermogenesis under b-adrenergic control might be more effective than targeting SCD1 alone are potential avenues for future research in obesity management. Keywords: thermogenesis; type 2 diabetes; sympathetic nervous system; catecholaminesThe sympathoadrenal system, through the release of norepinephrine from sympathetic nerves innervating peripheral tissues and through circulatory epinephrine released by adrenal medulla, plays an important role in the regulation of mammalian heat production. 1,2 Whereas in large mammals, the sites and molecular mechanisms underlying adrenergic control of heat production are poorly understood, studies in small rodents have implicated an elevation in sympathetic nervous system (SNS) activity in brown adipose tissue (BAT) -via b-adrenoceptor activation of its uncoupling protein (UCP1) -as a common mechanism for the stimulation of thermogenesis in response to both dietary and cold stimuli. 3,4 This contention is supported by the demonstrations that both SNS activity and UCP1 are elevated in BAT from rats and mice exhibiting adaptive increases in thermogenesis in response to cold or to overfeeding, and conversely they are both diminished in BAT from animals showing adaptive suppression of thermogenesis in response to fasting or severe food restriction. A major role for the SNS-BAT-UCP1 axis in thermoregulatory thermogenesis is further supported by the demonstration that mice lacking badrenoceptors (i.e. b-less mice) and mice deficient in UCP1 show impaired thermogenesis and poor tolerance to cold exposure. [5][6][7] However, the findings that only the b-less mice, but not the UCP1-deficient mice, are highly susceptible to develop obesity have also underscored the existence, even in small rodents, of mechanisms other than the SNS-BAT-UCP1 ...

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Elevated stearoyl-CoA desaturase-1 expression in skeletal muscle contributes to abnormal fatty acid partitioning in obese humans

Cited by 331 publications

References 51 publications

Intramyocellular lipid accumulation is associated with permanent relocation ex vivo and in vitro of fatty acid translocase (FAT)/CD36 in obese patients

Intramyocellular lipid accumulation is associated with permanent relocation ex vivo and in vitro of fatty acid translocase (FAT)/CD36 in obese patients

Increased Secretion and Expression of Myostatin in Skeletal Muscle From Extremely Obese Women

β-Adrenergic control of stearoyl-CoA desaturase 1 repression in relation to sympathoadrenal regulation of thermogenesis

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