Obese adipocytes show ultrastructural features of stressed cells and die of pyroptosisWe previously suggested that, in obese animals and humans, white adipose tissue inflammation results from the death of hypertrophic adipocytes; these are then cleared by macrophages, giving rise to distinctive structures we denominated crown-like structures. Here we present evidence that subcutaneous and visceral hypertrophic adipocytes of leptin-deficient (ob/ob and db/db) obese mice exhibit ultrastructural abnormalities (including calcium accumulation and cholesterol crystals), many of which are more common in hyperglycemic db/db versus normoglycemic ob/ob mice and in visceral versus subcutaneous depots. Degenerating adipocytes whose intracellular content disperses in the extracellular space were also noted in obese mice; in addition, increased anti-reactive oxygen species enzyme expression in obese fat pads, documented by RT-PCR and immunohistochemistry, suggests that ultrastructural changes are accompanied by oxidative stress. RT-PCR showed NLRP3 inflammasome activation in the fat pads of both leptin-deficient and high-fat diet obese mice, in which formation of active caspase-1 was documented by immunohistochemistry in the cytoplasm of several hypertrophic adipocytes. Notably, caspase-1 was not detected in FAT-ATTAC transgenic mice, where adipocytes die of apoptosis. Thus, white adipocyte overexpansion induces a stress state that ultimately leads to death. NLRP3-dependent caspase-1 activation in hypertrophic adipocytes likely induces obese adipocyte death by pyroptosis, a proinflammatory programmed cell death. We previously suggested that, in obese animals and humans, white adipose tissue inflammation results from the death of hypertrophic adipocytes; these are then cleared by macrophages, giving rise to distinctive structures we denominated crown-like structures. Here we present evidence that subcutaneous and visceral hypertrophic adipocytes of leptin-deficient (ob/ob and db/db) obese mice exhibit ultrastructural abnormalities (including calcium accumulation and cholesterol crystals), many of which are more common in hyperglycemic db/db versus normoglycemic ob/ob mice and in visceral versus subcutaneous depots. Degenerating adipocytes whose intracellular content disperses in the extracellular space were also noted in obese mice; in addition, increased anti-reactive oxygen species enzyme expression in obese fat pads, documented by RT-PCR and immunohistochemistry, suggests that ultrastructural changes are accompanied by oxidative stress. RT-PCR showed NLRP3 inflammasome activation in the fat pads of both leptin-deficient and high-fat diet obese mice, in which formation of active caspase-1 was documented by immunohistochemistry in the cytoplasm of several hypertrophic adipocytes. Notably, caspase-1 was not detected in FAT-ATTAC transgenic mice, where adipocytes die of apoptosis. Thus, white adipocyte overexpansion induces a stress state that ultimately leads to death. NLRP3-dependent caspase-1 activation in hypertrophic adipocytes likely induces obese adipocyte death by pyroptosis, a proinflammatory programmed cell death. Obesity results from a sustained imbalance between caloric intake and energy expenditure processes. In a state of caloric excess, white adipose tissue (WAT) plays a critical role by storing the surplus energy in the form of triglycerides, white adipocytes increase in number and size, and subcutaneous and visceral adipose depots expand. When adipose tissue enlargement is no longer capable of buffering the excess nutrients, numerous interconnected cell and tissue abnormalities arise, mainly in the visceral depots (1Olefsky J.M. Glass C.K. Macrophages, inflammation, and insulin resistance.Annu. Rev. Physiol. 2010; 72: 219-246Crossref PubMed Scopus (1977) Google Scholar, 2Item F. Konrad D. Visceral fat and metabolic inflammation: the portal theory revisited.Obes. Rev. 2012; 13: 30-39Crossref PubMed Scopus (149) Google Scholar, 3Johnson A.M.F. Olefsky J.M. The origins and drivers of insulin resistance.Cell. 2013; 152: 673-684Abstract Full Text Full Text PDF PubMed Scopus (451) Google Scholar–4Smorlesi A. Frontini A. Giordano A. Cinti S. The adipose organ: white-brown adipocyte plasticity and metabolic inflammation.Obes. Rev. 2012; 13: 83-96Crossref PubMed Scopus (125) Google Scholar). Increased catabolism in the mitochondria of hypertrophic adipocytes leads to oxidative stress and production of free radicals (5Patti M.E. Corvera S. The role of mitochondria in the pathogenesis of type 2 diabetes.Endocr. Rev. 2010; 31: 364-395Crossref PubMed Scopus (398) Google Scholar, 6Codoner-Franch P. Valls-Bellés V. Arilla-Codoner A. Alonso-Iglesias E. Oxidant mechanisms in childhood obesity: the link between inflammation and oxidative stress.Transl. Res. 2011; 158: 369-384Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar). When the adipocyte endoplasmic reticulum can no longer process the excess nutrients, “endoplasmic reticulum stress” develops (7Hummasti S. Hotamisligil G.S. Endoplasmic reticulum stress and inflammation in obesity and diabetes.Circ. Res. 2010; 107: 579-591Crossref PubMed Scopus (328) Google Scholar). Both mechanisms strongly contribute to adipose tissue inflammation, and the efflux of free fatty acids from adipocytes into the circulation causes lipid overload in skeletal muscle, liver, and pancreas. Additionally, failure of the vasculature to expand with adipocyte enlargement induces adipose tissue hypoxia (8Corvera S. Czech M.P. Tensions rise and blood flows over dysfunctional fat.Circulation. 2011; 124: 13-16Crossref PubMed Scopus (5) Google Scholar, 9Hardy O.T. Czech M.P. Corvera S. What causes the insulin resistance underlying obesity?.Curr. Opin. Endocrinol. Diabetes Obes. 2012; 19: 81-87Crossref PubMed Scopus (309) Google Scholar–10Trayhurn P. Hypoxia and adipose tissue function and dysfunction in obesity.Physiol. Rev. 2013; 93: 1-21Crossref PubMed Scopus (533) Google Scholar); with the passing of time, this results in a local state of tissue fibrosis (11Halberg N. Khan T. Trujillo M.E. Wernstedt-Asterholm I. Attie A.D. Sherwani S. Wang Z.V. Landskroner-Eiger S. Dineen S. Magalang U.J. et al.Hypoxia-inducible factor 1alpha induces fibrosis and insulin resistance in white adipose tissue.Mol. Cell. Biol. 2009; 29: 4467-4483Crossref PubMed Scopus (614) Google Scholar, 12Divoux A. Clément K. Architecture and the extracellular matrix: the still unappreciated components of the adipose tissue.Obes. Rev. 2011; 12: e494-e503Crossref PubMed Scopus (140) Google Scholar). These phenomena are accompanied by abnormal release of fatty acids, adipokines, and proinflammatory molecules by adipose tissue that in turn leads to a constellation of conditions (central obesity, dyslipidemia, glucose intolerance, and hypertension), which have come to be referred to as metabolic syndrome (13Tchernof A. Després J.P. Pathophysiology of human visceral obesity: an update.Physiol. Rev. 2013; 93: 359-404Crossref PubMed Scopus (1428) Google Scholar). In obese animals and humans, WAT is infiltrated by macrophages; the degree of infiltration significantly and positively correlates with white adipocyte size and results in the onset of insulin resistance (14Xu H. Barnes G.T. Yang Q. Tan Yang D. A. et inflammation in fat plays a role in the of insulin PubMed Scopus Google Scholar, D. Obesity is with accumulation in adipose PubMed Scopus Google Scholar). the inflammation of obese fat insulin by and the production of proinflammatory as factor and F. Konrad D. Visceral fat and metabolic inflammation: the portal theory revisited.Obes. Rev. 2012; 13: 30-39Crossref PubMed Scopus (149) Google Scholar, 3Johnson A.M.F. Olefsky J.M. The origins and drivers of insulin resistance.Cell. 2013; 152: 673-684Abstract Full Text Full Text PDF PubMed Scopus (451) Google Scholar). The of obese adipose tissue are where adipocytes form distinctive structures that we have crown-like structures S. I. E. E. Wang S. death and function in adipose tissue of obese mice and Res. Full Text Full Text PDF PubMed Scopus Google Scholar). are of macrophages, into that adipocytes. which are of in tissue that the death of the obese adipocyte is a in obese adipose tissue and that is by infiltration whose function is to and adipocyte Thus, we have the that the inflammation in obese adipose tissue is sustained by the the extracellular space of adipocyte the lipid S. I. E. E. Wang S. death and function in adipose tissue of obese mice and Res. Full Text Full Text PDF PubMed Scopus Google Scholar). of visceral and subcutaneous fat depots from ob/ob and db/db obese mice that the depots are the of adipocyte death and infiltration H. adipose tissue and obesity PubMed Scopus Google Scholar, I. V. Cinti S. detected as crown-like are in visceral fat depots of obese Res. Full Text Full Text PDF PubMed Scopus Google a that the with visceral fat In this we by the of the hypertrophic adipocytes in the subcutaneous and visceral adipose of obese ob/ob and db/db mice, which and the form of numerous abnormalities in hypertrophic adipocytes that are with metabolic stress and in cell and The increased expression of anti-reactive oxygen species in the fat of obese mice with the oxidative stress state of hypertrophic adipocytes. The abnormal in the hypertrophic adipocytes are capable of inflammasome the inflammasome is in the adipose depots of both obese mice and in where obesity is by a high-fat diet the caspase-1 expression detected by immunohistochemistry in hypertrophic adipocytes from obese mice and by in obese leptin-deficient mice, to the that hypertrophic adipocytes die of and mice were from of and of FAT-ATTAC activation of mice were also Trujillo M.E. P. activation of a of and PubMed Scopus Google Scholar). were and a with free to and mice were the mice of from were and the mice the were and into with were a high-fat diet from from and from the were a diet from from and from these the of mice was and that of mice was were in with and and were by the of of were with an of and with in and visceral WAT depots were a and by in in a in were in cleared in and in in were from were with and to the were and size was as the adipocyte of adipocytes from of a and the Czech of the were with a a and were with a insulin was a glucose was the glucose The insulin resistance was the where and are glucose and subcutaneous and visceral adipose tissue were in in in and in an were with were with an with and with a of hypertrophic adipocytes was animals were of adipose of were a of to endoplasmic reticulum the of hypertrophic adipocytes calcium and and the of adipocytes. were with and in were in and 2 and then by the A. T. The of the to the of human Res. PubMed Scopus Google Scholar, A. T. F. F. intracellular structures of human PubMed Scopus Google Scholar). a were and with an were with a The were by A. S. and was of fat depots. was with a by in a a in were with to with and in a were with the a in were in a were and were and as the were with and in was the was was to calcium to et The calcium and PubMed Scopus Google with were and with a of in a were with with 2 and with was detected by T. and are the of in fibrosis of the Full Text Full Text PDF PubMed Scopus Google Scholar). tissue were and then in in in 2 in in and was with and to the of of was with a with in a of expression was in by expression as and and expression which not were and were to with by were in an in a of and the by of and where was in the was to expression was by the as an in and in were results were as changes in expression with the are as of the between were by and by the was with of was both ob/ob and db/db obese mice and fat and mice not were detected by white adipocytes in the subcutaneous and visceral fat depots of obese mice S. I. E. E. Wang S. death and function in adipose tissue of obese mice and Res. Full Text Full Text PDF PubMed Scopus Google Scholar). subcutaneous and visceral white adipocyte size was in ob/ob mice and in db/db mice with animals in with I. V. Cinti S. detected as crown-like are in visceral fat depots of obese Res. Full Text Full Text PDF PubMed Scopus Google Scholar). In addition, subcutaneous adipocytes were visceral adipocytes in both obese adipocyte in obese animals were are in obese versus and in a animals were are in obese versus and glucose and mice and in ob/ob mice, glucose were to in and the insulin and were significantly The db/db mice the these In in ob/ob mice, insulin db/db mice both and in obese glucose was significantly increased in db/db with and and were significantly in both ob/ob and db/db mice with and are animals in a glucose was significantly increased in db/db with and and were significantly in both ob/ob and db/db mice with and are animals of stress in obese we by the hypertrophic adipocytes These to with the adipose tissue and were and Trujillo M.E. P. activation of a of and PubMed Scopus Google Scholar, P. of and the of factor to increase adipocyte in Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, D. A. and that with intracellular lipid in Biol. PubMed Scopus Google Scholar). The was in hypertrophic in adipocytes the was and in visceral hypertrophic adipocytes was in adipocytes from both obese and mice, was significantly in the hypertrophic adipocytes of visceral depots Notably, mitochondria the size of mitochondria and were also In the of adipocytes of both obese the was and the number of these was in the visceral depots adipocytes were also by a hypertrophic and numerous and the of hypertrophic adipocytes was in visceral in subcutaneous fat of the ultrastructural of hypertrophic adipocytes in obese mice, which are in in the and the of an and are significantly with in visceral In subcutaneous fat the are not in db/db with the ultrastructural of calcium of the and was in hypertrophic adipocytes; in many this to to the lipid and of the of abnormal calcium in the hypertrophic adipocytes of obese mice hypertrophic adipocytes also with the ultrastructural of cholesterol of the and Scholar, of The extracellular hypertrophic adipocytes from the adipocytes. number of were in with the of the of hypertrophic adipocytes In with this increased was noted hypertrophic adipocytes in In addition, with showed an of the of hypertrophic adipocytes of excess energy in adipocytes results in stress and endoplasmic reticulum giving rise to oxidative stress and production (5Patti M.E. Corvera S. The role of mitochondria in the pathogenesis of type 2 diabetes.Endocr. Rev. 2010; 31: 364-395Crossref PubMed Scopus (398) Google Scholar, 6Codoner-Franch P. Valls-Bellés V. Arilla-Codoner A. Alonso-Iglesias E. Oxidant mechanisms in childhood obesity: the link between inflammation and oxidative stress.Transl. Res. 2011; 158: 369-384Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar). of mechanisms have by to the of and free production activation of the and (5Patti M.E. Corvera S. The role of mitochondria in the pathogenesis of type 2 diabetes.Endocr. Rev. 2010; 31: 364-395Crossref PubMed Scopus (398) Google Scholar). evidence of the stress state of hypertrophic adipocytes of obese mice, the expression of these was in the adipose depots of these RT-PCR showed significantly increased of in the subcutaneous and visceral fat of ob/ob mice and of in the subcutaneous and visceral adipose depots of ob/ob and db/db mice with mice expression was increased in the subcutaneous of ob/ob and db/db mice and in the visceral of db/db mice were detected in the cytoplasm of hypertrophic adipocytes by to RT-PCR was strongly in the of ob/ob mice adipocytes were of adipocytes that and cholesterol in the cytoplasm and that an of the content The that adipocytes were to hypertrophic adipocytes that be to Degenerating adipocytes were by by that were numerous in the visceral and subcutaneous fat depots of obese mice, in and mice, and in Degenerating adipocytes to into the as documented by both and of free lipid in the extracellular space and in suggested that the from adipocytes was by were also in adipocytes and in of lipid by adipocytes into the visceral fat of a db/db obese a adipocyte is several lipid into the extracellular lipid is by the numerous the of the In lipid cleared by a in an where adipocytes are lipid the lipid in the In the hypertrophic adipocytes of ob/ob and db/db mice a number of ultrastructural abnormalities of the abnormal size and and of and abnormal of and cholesterol and increased of in the extracellular that are of a stress was by the increased expression of of these were in hyperglycemic db/db mice with normoglycemic ob/ob animals and in visceral with subcutaneous adipose depots. these a of as adipocyte of hypertrophic adipocytes with lipid release into the extracellular of macrophages, and formation of and of The NLRP3 inflammasome is a that an intracellular the and the The NLRP3 inflammasome to be in obese local production of the proinflammatory and A. K. E. J.M. The inflammasome and insulin 2011; PubMed Scopus Google Scholar). In RT-PCR showed significantly increased NLRP3 and caspase-1 in the adipose depots of obese with Notably, the of which NLRP3 inflammasome activation oxidative stress A. I. oxidative stress to inflammasome 2010; PubMed Scopus Google were significantly increased in the subcutaneous and visceral adipose depots of obese mice cholesterol were detected in the cytoplasm of both hypertrophic and adipocytes. were also in that were to evidence that the were cleared by the obese adipose and cholesterol content positively in adipocytes A.D. tissue and cholesterol Res. Full Text PDF PubMed Google Scholar). Thus, the the fat the more cholesterol conditions cholesterol giving rise to P. H. G.S. et are and by cholesterol 2010; PubMed Scopus Google Scholar). are to the NLRP3 inflammasome P. H. G.S. et are and by cholesterol 2010; PubMed Scopus Google Scholar, K. K. E. S. the NLRP3 inflammasome in human a link between cholesterol and 2010; PubMed Scopus Google Scholar); formation in hypertrophic adipocytes be the critical NLRP3 inflammasome showed caspase-1 NLRP3 and in the cytoplasm of many hypertrophic adipocytes and in Notably, caspase-1 and was mainly in that were in to adipocyte that not be to production by also to of caspase-1 and from adipocytes. The of these in not to is in with this Notably, the inflammasome were in the adipocytes of mice in the adipocytes of FAT-ATTAC mice a transgenic of adipocyte death Trujillo M.E. P. activation of a of and PubMed Scopus Google Scholar, M.E. activation of of and tissue PubMed Scopus Google Scholar). that the in ob/ob and db/db mice were to the leptin-deficient the was to obese both visceral and subcutaneous WAT depots with of the WAT hypertrophic adipocytes that were and numerous in the visceral the adipocyte was in the and in the subcutaneous fat with the depots. were not in the fat of mice were detected in mice adipocytes; subcutaneous RT-PCR showed a increase of and in the fat not increase in NLRP3 and caspase-1 was in the visceral WAT of mice, NLRP3 and caspase-1 were increased in subcutaneous immunohistochemistry, NLRP3 and caspase-1 were detected in and in the cytoplasm of several subcutaneous and visceral hypertrophic adipocytes. In obese animals and humans, WAT is with a local infiltration of mainly macrophages, that rise to inflammation (14Xu H. Barnes G.T. Yang Q. Tan Yang D. A. et inflammation in fat plays a role in the of insulin PubMed Scopus Google Scholar, D. Obesity is with accumulation in adipose PubMed Scopus Google Scholar). evidence suggests that adipose tissue inflammation strongly correlates with the of insulin resistance to to a in and an increase in (1Olefsky J.M. Glass C.K. Macrophages, inflammation, and insulin resistance.Annu. Rev. Physiol. 2010; 72: 219-246Crossref PubMed Scopus (1977) Google Scholar, 2Item F. Konrad D. Visceral fat and metabolic inflammation: the portal theory revisited.Obes. Rev. 2012; 13: 30-39Crossref PubMed Scopus (149) Google Scholar, 3Johnson A.M.F. Olefsky J.M. The origins and drivers of insulin resistance.Cell. 2013; 152: 673-684Abstract Full Text Full Text PDF PubMed Scopus (451) Google Scholar–4Smorlesi A. Frontini A. Giordano A. Cinti S. The adipose organ: white-brown adipocyte plasticity and metabolic inflammation.Obes. Rev. 2012; 13: 83-96Crossref PubMed Scopus (125) Google Scholar). Thus, adipose tissue inflammation is a in the pathogenesis of metabolic the that and the state We previously showed that the of obese adipose tissue are adipocyte giving rise to that we S. I. E. E. Wang S. death and function in adipose tissue of obese mice and Res. Full Text Full Text PDF PubMed Scopus Google Scholar). to of hypertrophic adipocytes by we that the death of hypertrophic adipocytes be the and adipose tissue inflammation in obese mice and Notably, of a in white results in increased lipid and white adipocyte a mice adipocyte not increased adipose obesity N. E. The adipose tissue of in Res. PubMed Scopus Google Scholar). in mice, we with a to the in obese fat S. I. E. E. Wang S. death and function in adipose tissue of obese mice and Res. Full Text Full Text PDF PubMed Scopus Google Scholar). that adipocyte death is a and suggests that the mechanisms adipocyte death are not to the obese to adipocyte a between adipocyte size and degree of documented in the subcutaneous and visceral adipose depots of obese mice (14Xu H. Barnes G.T. Yang Q. Tan Yang D. A. et inflammation in fat plays a role in the of insulin PubMed Scopus Google Scholar, D. Obesity is with accumulation in adipose PubMed Scopus Google Scholar, I. V. Cinti S. detected as crown-like are in visceral fat depots of obese Res. Full Text Full Text PDF PubMed Scopus Google Scholar). the that visceral fat adipocytes are of subcutaneous fat that is in the visceral fat of obese animals I. V. Cinti S. detected as crown-like are in visceral fat depots of obese Res. Full Text Full Text PDF PubMed Scopus Google suggested to that enlargement of white adipocytes a critical size in death. The present documented and of oxidative stress in the hypertrophic adipocytes of obese results in release of the content into the extracellular and leads to and and adipocyte changes were more in the hyperglycemic db/db the normoglycemic ob/ob are in db/db ob/ob mice I. V. Cinti S. detected as crown-like are in visceral fat depots of obese Res. Full Text Full Text PDF PubMed Scopus Google Scholar, of adipose depots in of obese Res. 13: Full Text PDF PubMed Google Scholar). between adipocyte size and fat inflammation documented D. Obesity is with accumulation in adipose PubMed Scopus Google Scholar, I. V. Cinti S. detected as crown-like are in visceral fat depots of obese Res. Full Text Full Text PDF PubMed Scopus Google as a between fat inflammation and insulin resistance (1Olefsky J.M. Glass C.K. Macrophages, inflammation, and insulin resistance.Annu. Rev. Physiol. 2010; 72: 219-246Crossref PubMed Scopus (1977) Google Scholar, 2Item F. Konrad D. Visceral fat and metabolic inflammation: the portal theory revisited.Obes. Rev. 2012; 13: 30-39Crossref PubMed Scopus (149) Google Scholar, 3Johnson A.M.F. Olefsky J.M. The origins and drivers of insulin resistance.Cell. 2013; 152: 673-684Abstract Full Text Full Text PDF PubMed Scopus (451) Google Scholar–4Smorlesi A. Frontini A. Giordano A. Cinti S. The adipose organ: white-brown adipocyte plasticity and metabolic inflammation.Obes. Rev. 2012; 13: 83-96Crossref PubMed Scopus (125) Google Scholar). We noted that visceral fat inflammation in db/db mice, as was that in ob/ob mice I. V. Cinti S. detected as crown-like are in visceral fat depots of obese Res. Full Text Full Text PDF PubMed Scopus Google Scholar). Thus, the of db/db mice to insulin resistance and can be by fat of the of the changes in FAT-ATTAC mice, in which white adipocyte is of a Trujillo M.E. P. activation of a of and PubMed Scopus Google Scholar, M.E. activation of of and tissue PubMed Scopus Google an of adipocytes exhibit then and and and are by in I. J.M. Wang Cinti S. of changes in adipose tissue 2012; Full Text Full Text PDF PubMed Scopus Google Scholar). Thus, the death of hypertrophic adipocytes to be a and formation in both obesity and in the adipose a of intracellular that are not in the to the of also in inflammation by molecules cell and tissue NLRP3 is the of the NLRP3 the and NLRP3 activation results in production of which in turn the of the proinflammatory and which are as active In obesity, in obese mice (ob/ob and and in obese humans, the is in both visceral and subcutaneous fat and local production of and A. K. E. J.M. The inflammasome and insulin 2011; PubMed Scopus Google Scholar, T. P. A. et caspase-1 activation adipocyte and insulin 2010; 12: Full Text Full Text PDF PubMed Scopus Google Scholar). In is in obese and is also strongly in insulin by T. of in type 2 Opin. Endocrinol. Diabetes Obes. 2010; Google and in of insulin T. insulin resistance in adipocytes of insulin PubMed Scopus Google Scholar). Notably, of by a human in with A. A. T. in type 2 PubMed Scopus Google and of to mice with obesity D. H. T. with an in PubMed Scopus Google to a sustained of inflammation and to significantly NLRP3-dependent caspase-1 activation and production of a role in metabolic syndrome in mice which are to the of high-fat obesity and insulin resistance D. A. I. et is a in the of obesity and insulin 2011; PubMed Scopus Google Scholar). are are by inflammasome and to inflammation cell death F. and of PubMed Scopus Google Scholar). is a proinflammatory whose can in a form of cell death as T. cell death and Rev. 2009; PubMed Scopus Google Scholar). the is by and release of proinflammatory is as a form of programmed cell is from which is an programmed cell death. the mechanisms this process are not the of to increase with inflammasome K. The 2010; Full Text Full Text PDF PubMed Scopus Google Scholar). We NLRP3 inflammasome activation and the of active caspase-1 in adipose tissue in leptin-deficient and obese and caspase-1 were detected by immunohistochemistry in the as by A. K. E. J.M. The inflammasome and insulin 2011; PubMed Scopus Google was also in hypertrophic adipocytes. is in with in that caspase-1 is adipocyte and adipocytes a more T. P. A. et caspase-1 activation adipocyte and insulin 2010; 12: Full Text Full Text PDF PubMed Scopus Google and with in of caspase-1 in the fat of ob/ob mice caspase-1 and in human adipose 2011; PubMed Scopus Google Scholar). distinctive ultrastructural of the hypertrophic and adipocytes in this were cholesterol in the a link not a capable of the NLRP3 inflammasome P. H. G.S. et are and by cholesterol 2010; PubMed Scopus Google Scholar, K. K. E. S. the NLRP3 inflammasome in human a link between cholesterol and 2010; PubMed Scopus Google Scholar). be that NLRP3 inflammasome activation in hypertrophic adipocytes is by the cholesterol which ultimately to in FAT-ATTAC mice, the of cell death of hypertrophic adipocytes is not by formation of cholesterol I. J.M. Wang Cinti S. of changes in adipose tissue 2012; Full Text Full Text PDF PubMed Scopus Google Scholar); the hypertrophic adipose tissue no of NLRP3 inflammasome caspase-1 activation from that, in to cholesterol the NLRP3 inflammasome in hypertrophic extracellular and glucose which of adipocyte cell A. I. oxidative stress to inflammasome 2010; PubMed Scopus Google Scholar, S. K. K. the inflammasome in to and PubMed Scopus Google and increased and free as also suggested by the increased expression of detected in tissue The is with the increased expression of in the adipose tissue of obese mice A. I. oxidative stress to inflammasome 2010; PubMed Scopus Google Scholar). increased intracellular also to the NLRP3 inflammasome G.S. N. I. The the NLRP3 inflammasome and 2012; PubMed Scopus Google Scholar). In the evidence in the present to the that, in obesity, hypertrophic adipocytes exhibit ultrastructural and cholesterol and accumulation of calcium and that the NLRP3 inflammasome with activation of which ultimately results in adipocyte death from the of cell of macrophages, whose and sustained in obese fat is to the extracellular space of lipid cholesterol by adipocytes. In the visceral fat of obese mice, this process can be by the death size of hypertrophic a the more with visceral fat suggested that the inflammation in obesity to the of into the circulation D. F. et obesity and insulin PubMed Scopus Google in factor activation in adipocytes and release of proinflammatory T. N. et of production in adipocytes by extracellular PubMed Scopus Google Scholar). the distinctive and the of to a of adipocyte and size as the of adipose tissue The are to A. and to in the of crown-like fat activation of high-fat diet endoplasmic reticulum oxygen species white adipose tissue