Immune Cell Crosstalk in Obesity: A Key Role for Costimulation?

Seijkens, Tom; Kusters, Pascal; Chatzigeorgiou, Antonios; Chavakis, Triantafyllos; Lutgens, Esther

doi:10.2337/db14-0272

Cited by 100 publications

(74 citation statements)

References 77 publications

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“…In summary, although a prior study suggests that obese patients derive a survival benefit, we show that they have significantly increased risk for several adverse transplant outcomes including delayed graft function, acute rejection and graft failure. Having higher levels of adipose tissue particularly in the abdominal area has been shown to promote a systemic proinflammatory state where both the humoral and cellular immune components work synergistically to promote inflammation [27–29] [30] [31]. Some possibilities from the current literature suggests antagonism of predominantly elevated proinflammatory cytokines such as TNFa, IL6, MCP1, IL2 can be explored as possible ways for immune modulation to decrease systemic inflammation.…”

Section: Discussionmentioning

confidence: 99%

Effect of the Obesity Epidemic on Kidney Transplantation: Obesity Is Independent of Diabetes as a Risk Factor for Adverse Renal Transplant Outcomes

et al. 2016

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BackgroundObesity is a growing epidemic in most developed countries including the United States resulting in an increased number of obese patients with end-stage renal disease. A previous study has shown that obese patients with end-stage renal disease have a survival benefit with transplantation compared with dialysis. However, due to serious comorbidities, many centers place restrictions on the selection of obese patients for transplantation. Further, due to obese patients having an increased risk of diabetes, it is unclear whether obesity can be an independent risk, independent of diabetes for increasing adverse renal transplant outcomes.MethodsTo investigate the role of obesity in kidney transplantation, we used the Scientific Registry of Transplant Recipients database. After filtering for subjects that had the full set of covariates including age, gender, graft type, ethnicity, diabetes, peripheral vascular disease, dialysis time and time period of transplantation for our analysis, 191,091 subjects were included in the analyses. Using multivariate logistic regression analyses adjusted for covariates we determined whether obesity is an independent risk factor for adverse outcomes such as delayed graft function, acute rejection, urine protein and graft failure. Cox regression modeling was used to determine hazard ratios of graft failure.ResultsUsing multivariate model analyses, we found that obese patients have significantly increased risk of adverse transplant outcomes, including delayed graft function, graft failure, urine protein and acute rejection. Cox regression modeling hazard ratios showed that obesity also increased risk of graft failure. Life-table survival curves showed that obesity may be a risk factor independent of diabetes mellitus for a shorter time to graft failure.ConclusionsA key observation in our study is that the risks for adverse outcome of obesity are progressive with increasing body mass index. Furthermore, pre-obese overweight recipients compared with normal weight recipients also had increased risks of adverse outcomes related to kidney transplantation.

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Section: Discussionmentioning

confidence: 99%

Effect of the Obesity Epidemic on Kidney Transplantation: Obesity Is Independent of Diabetes as a Risk Factor for Adverse Renal Transplant Outcomes

et al. 2016

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“…Such reduced GluOC levels might contribute to the lower serum concentration of testosterone in male mice fed an HFS diet than in those fed a normal diet, and therefore, they might be expected to be beneficial for glucose metabolism. However, intolerance to glucose and insulin triggered by a HFS diet is also caused by the release of inflammatory cytokines (adipokines) from hypertrophic adipocytes (47,48) and downregulation of the receptors for insulin and adiponectin (52), effects that likely mask any action of a reduced serum testosterone concentration. Fig.…”

Section: Discussionmentioning

confidence: 99%

Long-term oral administration of osteocalcin induces insulin resistance in male mice fed a high-fat, high-sucrose diet

Yasutake

Mizokami

Kawakubo‐Yasukochi

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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Long-term oral administration of osteocalcin induces insulin resistance in male mice fed a high-fat, highsucrose diet. Am J Physiol Endocrinol Metab 310: E662-E675, 2016. First published February 16, 2016 doi:10.1152/ajpendo.00334.2015.-Uncarboxylated osteocalcin (GluOC), a bone-derived hormone, regulates energy metabolism by stimulating insulin secretion, pancreatic ␤-cell proliferation, and adiponectin expression in adipocytes. Previously, we showed that long-term intermittent or daily oral administration of GluOC reduced the fasting blood glucose level, improved glucose tolerance, and increased the fasting serum insulin concentration as well as pancreatic ␤-cell area in female mice fed a normal or high-fat, high-sucrose diet. We have now performed similar experiments with male mice and found that such GluOC administration induced glucose intolerance, insulin resistance, and adipocyte hypertrophy in those fed a high-fat, high-sucrose diet. In addition, GluOC increased the circulating concentration of testosterone and reduced that of adiponectin in such mice. These phenotypes were not observed in male mice fed a high-fat, high-sucrose diet after orchidectomy, but they were apparent in orchidectomized male mice or intact female mice that were fed such a diet and subjected to continuous testosterone supplementation. Our results thus reveal a sex difference in the effects of GluOC on glucose homeostasis. Given that oral administration of GluOC has been considered a potentially safe and convenient option for the treatment or prevention of metabolic disorders, this sex difference will need to be taken into account in further investigations. adiponectin; insulin resistance; osteocalcin; sex difference; testosterone OSTEOCALCIN IS A BONE MATRIX PROTEIN synthesized by osteoblasts that also functions as a hormone in the uncarboxylated state to regulate various aspects of physiology, including glucose metabolism, brain function, and male fertility (14,17,30,39,40). Uncarboxylated osteocalcin (GluOC) constitutes ϳ10% of total circulating osteocalcin in adult mice under normal physiological conditions (2, 10). However, the serum concentration of GluOC is increased in pathological conditions such as vitamin K deficiency and osteoporosis (2,26,31). Animal studies have shown that an increase in the circulating concentration of GluOC prevents obesity and glucose intolerance (10,13,28,30). Mice genetically deficient in Esp (a protein tyrosine phosphatase expressed in osteoblasts), a gainof-function model for osteocalcin, were thus protected from obesity, glucose intolerance, and insulin resistance induced by a high-fat diet (14, 30). Continuous administration of GluOC via a subcutaneous osmotic pump lowered blood glucose levels and increased pancreatic ␤-cell mass, insulin secretion, and insulin sensitivity in mice with high-fat diet-or gold thioglucose-induced obesity, with this latter effect being achieved via upregulation of expression of the gene for the insulin-sensitizing adipokine adiponectin in adipocytes (10). Moreove...

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“…In particular, chronic inflammation in adipose tissue is an essential cause of obesity-induced insulin resistance (30,33). Adipocytes in the insulin-sensitive adipose tissue of lean subjects secret anti-inflammatory cytokines (34).…”

Section: Discussionmentioning

confidence: 99%

Protein Inhibitor of Activated STAT 1 (PIAS1) Protects Against Obesity-Induced Insulin Resistance by Inhibiting Inflammation Cascade in Adipose Tissue

Liu

Dou

et al. 2015

Diabetes

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Obesity is associated with chronic low-level inflammation, especially in fat tissues, which contributes to insulin resistance and type 2 diabetes mellitus (T2DM). Protein inhibitor of activated STAT 1 (PIAS1) modulates a variety of cellular processes such as cell proliferation and DNA damage responses. Particularly, PIAS1 functions in the innate immune system and is a key regulator of the inflammation cascade. However, whether PIAS1 is involved in the regulation of insulin sensitivity remains unknown. Here, we demonstrated that PIAS1 expression in white adipose tissue (WAT) was downregulated by c-Jun N-terminal kinase in prediabetic mice models. Overexpression of PIAS1 in inguinal WAT of prediabetic mice significantly improved systemic insulin sensitivity, whereas knockdown of PIAS1 in wild-type mice led to insulin resistance. Mechanistically, PIAS1 inhibited the activation of stress-induced kinases and the expression of nuclear factor-κB target genes in adipocytes, mainly including proinflammatory and chemotactic factors. In doing so, PIAS1 inhibited macrophage infiltration in adipose tissue, thus suppressing amplification of the inflammation cascade, which in turn improved insulin sensitivity. These results were further verified in a fat transplantation model. Our findings shed light on the critical role of PIAS1 in controlling insulin sensitivity and suggest a therapeutic potential of PIAS1 in T2DM.

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Immune Cell Crosstalk in Obesity: A Key Role for Costimulation?

Cited by 100 publications

References 77 publications

Effect of the Obesity Epidemic on Kidney Transplantation: Obesity Is Independent of Diabetes as a Risk Factor for Adverse Renal Transplant Outcomes

Effect of the Obesity Epidemic on Kidney Transplantation: Obesity Is Independent of Diabetes as a Risk Factor for Adverse Renal Transplant Outcomes

Long-term oral administration of osteocalcin induces insulin resistance in male mice fed a high-fat, high-sucrose diet

Protein Inhibitor of Activated STAT 1 (PIAS1) Protects Against Obesity-Induced Insulin Resistance by Inhibiting Inflammation Cascade in Adipose Tissue

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