The adipokine/ceramide axis: Key aspects of insulin sensitization

Xia, Jonathan Y.; Morley, Thomas S.; Scherer, Philipp E.

doi:10.1016/j.biochi.2013.08.013

Cited by 48 publications

(52 citation statements)

References 103 publications

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“…Some evidence suggests that ceramides increase both adipokine expression and its level in the circulation [48]. Available data indicate a strong link between ceramides and adipokines [48,76]. Hamada et al [76] showed that ceramides stimulate pro-inflammatory adipokine secretion as well as IL-6 and monocyte chemo-attractant protein-1 in mature 3T3-L1 adipocytes.…”

Section: Ceramide and Adipokines Expression/releasementioning

confidence: 99%

Ceramides and diabetes mellitus: an update on the potential molecular relationships

Yaribeygi

Ruscica

et al. 2019

Diabet. Med.

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Recent evidence suggests that ceramides can play an important pathophysiological role in the development of diabetes. Ceramides are primarily recognized as lipid bilayer building blocks, but recent work has shown that these endogenous molecules are important intracellular signalling mediators and may exert some diabetogenic effects via molecular pathways involved in insulin resistance, β‐cell apoptosis and inflammation. In the present review, we consider the available evidence on the possible roles of ceramides in diabetes mellitus and introduce eight different molecular mechanisms mediating the diabetogenic action of ceramides, categorized into those predominantly related to insulin resistance vs those mainly implicated in β‐cell dysfunction. Specifically, the mechanistic evidence involves β‐cell apoptosis, pancreatic inflammation, mitochondrial stress, endoplasmic reticulum stress, adipokine release, insulin receptor substrate 1 phosphorylation, oxidative stress and insulin synthesis. Collectively, the evidence suggests that therapeutic agents aimed at reducing ceramide synthesis and lowering circulating levels may be beneficial in the prevention and/or treatment of diabetes and its related complications.

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Section: Ceramide and Adipokines Expression/releasementioning

confidence: 99%

Ceramides and diabetes mellitus: an update on the potential molecular relationships

Yaribeygi

Ruscica

et al. 2019

Diabet. Med.

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“…De novo ceramide synthesis occurs in the endoplasmic reticulum, but ceramide is then transported to the golgi where it can serve as a substrate for more complex sphingolipids, sphingomyelin and ceramide-1-phosphate [62]. Ceramide can also be generated through the hydrolysis of sphingomyelin (salvage pathway) or synthesis from sphingosine and more complex sphingolipids (recycling pathway) [62, 63]. Lipids and ceramides are not only key structural components of the cell, but also have the potential to activate the Nlrp3 inflammasome [64].…”

Section: (3) Metabolites As Dampsmentioning

confidence: 99%

Regulation of Nlrp3 inflammasome by dietary metabolites

Camell

Goldberg

Dixit

2015

Seminars in Immunology

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The bidirectional communication between innate immune cells and energy metabolism is now widely appreciated to regulate homeostasis as well as chronic diseases that emerge from dysregulated inflammation. Macronutrients-derived from diet or endogenous pathways that generate and divert metabolites into energetic or biosynthetic pathways-regulate the initiation, duration and cessation of the inflammatory response. The NLRP3 inflammasome is an important innate sensor of structurally diverse metabolic damage-associated molecular patterns (DAMPs) that has been implicated in a wide range of inflammatory disorders associated with caloric excess, adiposity and aging. Understanding the regulators of immune-metabolic interactions and their contribution towards chronic disease mechanisms, therefore, has the potential to reduce disease pathology, improve quality of life in elderly and promote the extension of healthspan. Just as specialized subsets of immune cells dampen inflammation through the production of negative regulatory cytokines; specific immunoregulatory metabolites can deactivate inflammasome-mediated immune activation. Here, we highlight the role of energy substrates, alternative fuels and metabolic DAMPs in the regulation of the NLRP3 inflammasome and discuss potential dietary interventions that may impact sterile inflammatory disease.

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“…A series of studies have shown that increased ceramide levels in both liver and plasma coincide with the development of liver dysfunction, hepatic insulin resistance, and steatosis in rodents (Ichi et al, 2007; Xia et al, 2014; Yetukuri et al, 2007). Previous work has identified the liver as a target of ceramide-induced insulin resistance and inhibition of whole-body ceramide synthesis reduces obesity-induced insulin resistance in rodents (Holland et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…In particular, ceramides derived from C16 fatty acids appear to oppose insulin action most potently (Raichur et al, 2014; Turpin et al, 2014). Breakdown of ceramides are initiated by enzymes called ceramidases, which are categorized by homology and pH optima at which they can hydrolyze ceramides into sphingosines and free fatty acids (Xia et al, 2014). The anti-diabetic and anti-steatotic adipokine, adiponectin rapidly lowers hepatic ceramide content, thereby improving glucose homeostasis through its receptor-associated ceramidase activity (Holland et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Targeted Induction of Ceramide Degradation Leads to Improved Systemic Metabolism and Reduced Hepatic Steatosis

et al. 2015

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Sphingolipids have garnered attention for their role in insulin resistance and lipotoxic cell death. Aberrant accumulation of ceramides correlates with hepatic insulin resistance and steatosis. To further investigate the tissue-specific effects of local changes in ceramidase activity, we have developed transgenic mice inducibly expressing acid ceramidase, to trigger the deacylation of ceramides. This represents the first inducible genetic model that acutely manipulates ceramides in adult mouse tissues. Hepatic overexpression of acid ceramidase prevents hepatic steatosis and prompts improvements in insulin action in liver and adipose tissue. Conversely, overexpression of acid ceramidase within adipose tissue prevents hepatic steatosis and insulin resistance. Induction of ceramidase activity in either tissue promotes a lowering of hepatic ceramides and reduced activation of the ceramide-activated protein kinase C isoform PKC-zeta. These observations suggest the existence of a rapidly acting "crosstalk" between liver and adipose tissue sphingolipids, critically regulating glucose metabolism and hepatic lipid uptake.

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The adipokine/ceramide axis: Key aspects of insulin sensitization

Cited by 48 publications

References 103 publications

Ceramides and diabetes mellitus: an update on the potential molecular relationships

Ceramides and diabetes mellitus: an update on the potential molecular relationships

Regulation of Nlrp3 inflammasome by dietary metabolites

Targeted Induction of Ceramide Degradation Leads to Improved Systemic Metabolism and Reduced Hepatic Steatosis

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