CerS1-Derived C18:0 Ceramide in Skeletal Muscle Promotes Obesity-Induced Insulin Resistance

Turpin-Nolan, Sarah M.; Hammerschmidt, Philipp; Chen, Weiyi; Jais, Alexander; Timper, Katharina; Awazawa, Motoharu; Brodesser, Susanne; Brüning, Jens C.

doi:10.1016/j.celrep.2018.12.031

Cited by 141 publications

(143 citation statements)

References 38 publications

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“…SPHK1 is involved in the phosphorylation of the long chain base sphingosine to sphingosine-1-phosphate, and SMPD2 and SMPDL3B in the hydrolysis of the phospholipid sphingomyelin into ceramide and phosphocholine (24). CERS1 produces ceramides with a C18:0 acyl chain length shown to influence obesity-related IR in skeletal muscle (25). The differential regulation of SL-metabolism genes is consistent with the different lipid exposure from BTWT and SLMUT.…”

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confidence: 59%

Sphingolipid production by gut Bacteroidetes regulates glucose homeostasis

Johnson

Heaver

Waters

et al. 2019

Preprint

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Levels of Bacteroidetes in the gut microbiome are positively associated with insulin resistance (IR) in humans. Considering that IR is promoted by elevations in hepatic sphingolipids (SL), particularly ceramides, and that Bacteroidetes are the only microbiome phylum possessing genes encoding serine palmitoyltransferase (SPT), which mediates SL synthesis, we investigated a potential link between bacterial SL production, host SL metabolism, and IR. In vitro, bacterial SLs entered colonocytes and were metabolized into complex SL, including ceramides. In mice, administration of WT Bacteroides thetaiotaomicron, but not a SPT-deficient mutant, resulted in elevated levels of liver ceramides and reduced responsiveness to exogenously administered insulin. This work establishes bacterial SLs as a new class of microbiome-derived molecule capable of impacting host metabolism.One Sentence Summary: SL production by gut Bacteroidetes regulates liver ceramide levels and insulin sensitivity.Main Text: Insulin resistance (IR) is a hallmark of metabolic syndrome, the precursor to type 2 diabetes.Ceramides, which are an important class of complex sphingolipids (SLs), have been implicated in the development of IR in animal models (1). Reduction of ceramide (d18:1/16:0) in the liver alleviates IR (2-4), and pharmacological inhibition of ceramide-related pathways in the intestine leads to improved glucose homeostasis (5). In human populations, several studies have associated levels of hepatic or plasma ceramides to IR (6-9), suggesting that an understanding of how ceramide pools are regulated could be beneficial for treatment. Sources of SL include de novo synthesis, degradation and recycling of existing SLs, and uptake of dietary SLs from the intestine. We hypothesized that the gut microbiome constitutes an additional source of SL with impact on host SL homeostasis.The human gut microbiome comprises a vast diversity of bacterial species that varies between individuals, however across individuals a small number of bacterial phyla are proportionally dominant.

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confidence: 59%

Sphingolipid production by gut Bacteroidetes regulates glucose homeostasis

Johnson

Heaver

Waters

et al. 2019

Preprint

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“…The reduced caliber sizes were most pronounced in the extensor digitorum longus (EDL) from CerS5 Δ/Δ mice, which corresponded well with reduced twitch and tetanus forces. Lack of CerS1 or CerS5 has been associated with improvement of systemic glucose homeostasis via increase in Fgf21 from skeletal muscle (Turpin‐Nolan et al, ) and insulin resistance (Gosejacob et al, ), respectively, indicating that the negative effects of CerS1 and CerS5 on skeletal muscle fiber size and strength are not secondary to insulin resistance. Together, our results demonstrate an age‐associated, selective, and significant loss of C 16:0 and C 18:0 ceramides and a corresponding decline of CerS1 and CerS5 in skeletal muscle of humans and mice.…”

Section: Discussionmentioning

confidence: 99%

“…The levels of CerS2 mRNA were significantly smaller, and CerS4‐6 levels were greater in gastric smooth muscle of aged mice associated with contractile dysfunction (Choi et al, ). In skeletal muscle of mice fed with high‐fat diet, CerS1‐derived C18 ceramide promoted systemic insulin resistance (Turpin‐Nolan et al, ), indicating an impact of ceramide in skeletal muscle metabolism.…”

Section: Introductionmentioning

confidence: 99%

A tissue‐specific screen of ceramide expression in aged mice identifies ceramide synthase‐1 and ceramide synthase‐5 as potential regulators of fiber size and strength in skeletal muscle

et al. 2019

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Loss of skeletal muscle mass is one of the most widespread and deleterious processes in aging humans. However, the mechanistic metabolic principles remain poorly understood. In the framework of a multi‐organ investigation of age‐associated changes of ceramide species, a unique and distinctive change pattern of C16:0 and C18:0 ceramide species was detected in aged skeletal muscle. Consistently, the expression of CerS1 and CerS5 mRNA, encoding the ceramide synthases (CerS) with substrate preference for C16:0 and C18:0 acyl chains, respectively, was down‐regulated in skeletal muscle of aged mice. Similarly, an age‐dependent decline of both CerS1 and CerS5 mRNA expression was observed in skeletal muscle biopsies of humans. Moreover, CerS1 and CerS5 mRNA expression was also reduced in muscle biopsies from patients in advanced stage of chronic heart failure (CHF) suffering from muscle wasting and frailty. The possible impact of CerS1 and CerS5 on muscle function was addressed by reversed genetic analysis using CerS1Δ/Δ and CerS5Δ/Δ knockout mice. Skeletal muscle from mice deficient of either CerS1 or CerS5 showed reduced caliber sizes of both slow (type 1) and fast (type 2) muscle fibers, fiber grouping, and fiber switch to type 1 fibers. Moreover, CerS1‐ and CerS5‐deficient mice exhibited reduced twitch and tetanus forces of musculus extensor digitorum longus. The findings of this study link CerS1 and CerS5 to histopathological changes and functional impairment of skeletal muscle in mice that might also play a functional role for the aging skeletal muscle and for age‐related muscle wasting disorders in humans.

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“…[2][3][4][5][6][7][8] Activation of these transcriptional factors enhanced mitochondrial biogenesis leads to dramatically increased endurance, ameliorated insulin resistance in obesity, and type 2 diabetes. [9][10][11][12][13] It has been known that mitochondrial dysfunction and cellular oxidative stress induced by excess energy states and elevations in circulating free fatty acid (FFA) are associated with insulin resistance in skeletal muscle. [14][15][16][17][18][19][20] Therefore, in order to improve skeletal muscle insulin resistance and energy expenditure, it is important to stimulate mitochondrial biogenesis to preserve mitochondrial pool and to increase mitochondrial oxidative phosphorylation and FFA metabolism.…”

Section: Introductionmentioning

confidence: 99%

Astaxanthin stimulates mitochondrial biogenesis in insulin resistant muscle via activation of AMPK pathway

Nishida

Nawaz

Kado

et al. 2020

J cachexia sarcopenia muscle

110

125

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Background Skeletal muscle is mainly responsible for insulin‐stimulated glucose disposal. Dysfunction in skeletal muscle metabolism especially during obesity contributes to the insulin resistance. Astaxanthin (AX), a natural antioxidant, has been shown to ameliorate hepatic insulin resistance in obese mice. However, its effects in skeletal muscle are poorly understood. The current study aimed to investigate the molecular target of AX in ameliorating skeletal muscle insulin resistance. Methods We fed 6‐week‐old male C57BL/6J mice with normal chow (NC) or NC supplemented with AX (NC+AX) and high‐fat‐diet (HFD) or HFD supplemented with AX for 24 weeks. We determined the effect of AX on various parameters including insulin sensitivity, glucose uptake, inflammation, kinase signaling, gene expression, and mitochondrial function in muscle. We also determined energy metabolism in intact C2C12 cells treated with AX using the Seahorse XFe96 Extracellular Flux Analyzer and assessed the effect of AX on mitochondrial oxidative phosphorylation and mitochondrial biogenesis. Results AX‐treated HFD mice showed improved metabolic status with significant reduction in blood glucose, serum total triglycerides, and cholesterol (p< 0.05). AX‐treated HFD mice also showed improved glucose metabolism by enhancing glucose incorporation into peripheral target tissues, such as the skeletal muscle, rather than by suppressing gluconeogenesis in the liver as shown by hyperinsulinemic–euglycemic clamp study. AX activated AMPK in the skeletal muscle of the HFD mice and upregulated the expressions of transcriptional factors and coactivator, thereby inducing mitochondrial remodeling, including increased mitochondrial oxidative phosphorylation component and free fatty acid metabolism. We also assessed the effects of AX on mitochondrial biogenesis in the siRNA‐mediated AMPK‐depleted C2C12 cells and showed that the effect of AX was lost in the genetically AMPK‐depleted C2C12 cells. Collectively, AX treatment (i) significantly ameliorated insulin resistance and glucose intolerance through regulation of AMPK activation in the muscle, (ii) stimulated mitochondrial biogenesis in the muscle, (iii) enhanced exercise tolerance and exercise‐induced fatty acid metabolism, and (iv) exerted antiinflammatory effects via its antioxidant activity in adipose tissue. Conclusions We concluded that AX treatment stimulated mitochondrial biogenesis and significantly ameliorated insulin resistance through activation of AMPK pathway in the skeletal muscle.

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CerS1-Derived C18:0 Ceramide in Skeletal Muscle Promotes Obesity-Induced Insulin Resistance

Cited by 141 publications

References 38 publications

Sphingolipid production by gut Bacteroidetes regulates glucose homeostasis

Sphingolipid production by gut Bacteroidetes regulates glucose homeostasis

A tissue‐specific screen of ceramide expression in aged mice identifies ceramide synthase‐1 and ceramide synthase‐5 as potential regulators of fiber size and strength in skeletal muscle

Astaxanthin stimulates mitochondrial biogenesis in insulin resistant muscle via activation of AMPK pathway

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