The Inflammasome-Mediated Caspase-1 Activation Controls Adipocyte Differentiation and Insulin Sensitivity

By R. Stienstra, L. Joosten, Tim B. Koenen, Berry L J van Tits, J. V. van Diepen, S. V. D. van den Berg, P. Rensen, P. Voshol, Giamilla Fantuzzi, A. Hijmans and 10 more. Cell Metabolism, 2010

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SUMMARY Obesity-induced inflammation originating from expanding adipose tissue interferes with insulin sensitivity. Important metabolic effects have been recently attributed to IL-1β and IL-18, two members of the IL-1 family of cytokines. Processing of IL-1β and IL-18 requires cleavage by caspase-1, a cysteine protease regulated by a protein complex called the inflammasome. We demonstrate that the inflamma-some/caspase-1 governs adipocyte differentiation and insulin sensitivity. Caspase-1 is upregulated during adipocyte differentiation and directs adipocytes toward a more insulin-resistant phenotype. Treatment of differentiating adipocytes with recombinant IL-1β and IL-18, or blocking their effects by inhibitors, reveals that the effects of caspase-1 on adipocyte differentiation are largely conveyed by IL-1β. Caspase-1 and IL-1β activity in adipose tissue is increased both in diet-induced and genetically induced obese animal models. Conversely, mice deficient in caspase-1 are more insulin sensitive as compared to wild-type animals. In addition, differentiation of preadipocytes isolated from caspase-1−/− or NLRP3−/− mice resulted in more metabolically active fat cells. In vivo, treatment of obese mice with a caspase-1 inhibitor significantly increases their insulin sensitivity. Indirect calorimetry analysis revealed higher fat oxidation rates in caspase-1−/− animals. In conclusion, the inflammasome is an important regulator of adipocyte function and insulin sensitivity, and caspase-1 inhibition may represent a novel therapeutic target in clinical conditions associated with obesity and insulin resistance.

Subfields: Cardiology and Cardiovascular Medicine, Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/1449e4c1e864b86f957bea3e8be2c605cf8d1d63

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Citations in the corpus

Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders (2017, background): “More important, we provide evidence showing that directly targeting NLRP3 itself by CY-09 could inhibit NLRP3 inflammasome activation in vivo and had remarkable therapeutic effects on the mouse models of NLRP3-driven diseases, such as T2D and CAPS. reSuLtS cY-09 specifically blocks nLrP3 activation ”
NLRP6 inflammasome orchestrates the colonic host-microbial interface by regulating goblet cell mucus secretion. (2014, positive): “As an example, caspase-1/inflammasome signaling is essential in adipocyte differentiation and influencing insulin resistance in these cells (Stienstra et al., 2010).”
Chronic Adipose Tissue Inflammation Linking Obesity to Insulin Resistance and Type 2 Diabetes (2020, background): “…member of the NLR family) activation by DAMPs (generated by nutrient excess in obesity) plays a key role behind the chronic inflammation characteristic of obesity and IR (Stienstra et al., 2010, 2011, 2012; Zhou et al., 2010; Koenen et al., 2011; Vandanmagsar et al., 2011; Lee et al., 2013).”
Redox Regulation of NLRP3 Inflammasomes: ROS as Trigger or Effector? (2015, neutral): “In particular, the role of inflammasomes in the pathogenesis of metabolic syndrome is considered rather complicated and the notion that inflammasome activation contributes only to the inflammatory progression of disease may be oversimplified (49), especially when caspase-1mediated cleavage of glycol”
Inflammasome is a central player in the induction of obesity and insulin resistance (2011, background): “In line with our previous work (23), caspase-1 gene expression and activation in white adipose tissue (WAT) of HFD-fed wild-type mice were increased (Fig.”
Intestinal mucosal adherence and translocation of commensal bacteria at the early onset of type 2 diabetes: molecular mechanisms and probiotic treatment (2011, neutral): “Nlrp3 inﬂammasome senses lipotoxicity-associated increases in intracellular ceramide to induce caspase-1 cleavage in macrophages and adipose tissue (Stienstra et al, 2010; Vandanmagsar et al, 2011).”
NLRP3 inflammasome: From a danger signal sensor to a regulatory node of oxidative stress and inflammatory diseases (2015, background): “…LRR, leucine-rich-repeat olymorphonuclear leukocytes; POP, PYD-only proteins; PRRs, pattern-recognition MCs, smooth muscle cells; TLRs, toll-like receptors; TNF, tumor necrosis factor; Trx, unfolded protein response eing Biology (B2A), UMR-8256/INSERM ERL-1164, Université Pierre et Marie Curie,”
Kupffer Cells in the Liver (2013, neutral): “associated with metabolic syndrome (26, 130, 145), it is not known if there is a role for these NLRs in ALD.”