CD4+ T cells memorize obesity and promote weight regain

Zou, Jianghuan; Lai, Beibei; Zheng, Mingzhu; Qin, Chunxia; Jiang, Shujun; Song, Anying; Huang, Zan; Shi, Peiliang; Tu, Xin; Wang, Di; Lu, Linrong; Lin, Zhaoyu; Gao, Xiang

doi:10.1038/cmi.2017.36

Cited by 50 publications

(50 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, as is common in observational human studies, it is difficult to prove causality. However, considering the present findings and those from prior weight gain-loss obese mice studies (57), in which CD4 + T cells were shown to mediate obesity memory and promote weight regain, our results are highly suggestive of a similar relationship in humans. As the gut microbiota seems to be involved in the induction of obesity and interacts with the gut immune system (59), regulating the formation of effector memory T-cell subsets, studies investigating the modulation of the gut microbiome through diet, pre-and probiotics, antibiotics, surgery, and fecal transplantation are warranted.…”

Section: Discussionsupporting

confidence: 78%

White adipose tissue inflammation is not attenuated by short-term calorie restriction in obese humans

Sbierski-Kind

Mai

Kath

et al. 2019

Preprint

View full text Add to dashboard Cite

Obesity is a growing global health problem due to its association with chronic low-grade inflammation contributing to metabolic complications. Multiple studies indicate that white adipose tissue (WAT) inflammation can drive the pathogenesis of type 2 diabetes, including altered levels of cells of the innate and adaptive immune system. However, the function and regulation of both innate and adaptive immune cells in human WAT under conditions of obesity and calorie restriction (CR) is not fully understood yet. Using a randomized interventional design, we investigated postmenopausal obese women who either underwent CR for three months followed by a 4 weeks phase of weight maintenance or had to maintain a stable weight over the whole study period. A comprehensive immune phenotyping protocol was conducted using validated multiparameter flow cytometry analysis in blood and subcutaneous WAT (SAT) (n=21). The T cell receptor repertoire was analyzed by next generation sequencing (n=20) and cytokine levels were determined in SAT (n=22). Metabolic parameters were determined by hyperinsulinemic-euglycemic clamp and then correlated to immune cell subsets. We found that insulin resistance (IR) correlates significantly with a shift towards the memory T cell compartment in SAT. Among various T cell subsets, predominantly CD8+ effector memory T cells were associated with obesity-related IR. Interestingly, T cell receptor analysis revealed a diverse repertoire in SAT arguing against an antigen-driven intra-SAT expansion of effector memory T cells. Surprisingly, neither inflammatory cytokine levels nor leucocyte subpopulations were significantly altered upon CR. Our findings demonstrate the accumulation of effector memory T cells in obese SAT contributing to chronic inflammation. The long-standing effect of obesity-induced changes in SAT was demonstrated by preserved immune cell composition after short-term CR induced weight loss.

show abstract

Section: Discussionsupporting

confidence: 78%

White adipose tissue inflammation is not attenuated by short-term calorie restriction in obese humans

Sbierski-Kind

Mai

Kath

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Moreover, phenotypic switching of ATMs into the alternatively activated M2 is sufficient to modulate adipose tissue function. 22,42,43 In the eWAT of diabetic mice, miR-99a mimics significantly attenuated F4/80 + CD11b + CD11c + CD206 − M1 and enhanced the F4/80 + CD11b + CD11c − CD206 + M2 macrophage populations, while significantly decreasing iNOS, MCP-1, and TNFα and significantly increasing ARG-1, YM-1, and PPARγ mRNA expression. In miR-99a-treated db/db mice, an attenuated CD86 and enhanced CD301 staining in eWAT again suggested the suppression of M1 macrophage and activation of the M2 phenotype.…”

Section: Discussionmentioning

confidence: 98%

MicroRNA-99a mimics inhibit M1 macrophage phenotype and adipose tissue inflammation by targeting TNFα

et al. 2018

View full text Add to dashboard Cite

In human adipose tissue and obesity, miR-99a expression is negatively correlated with inflammation. Therefore, the present study investigated the role of miR-99a in macrophage phenotype activation and adipose tissue inflammation. M2 BMDMs showed a significant increase in miR-99a expression when compared to the M0 and M1 phenotypes. Phenotype-switching experiments established an association between upregulated miR-99a expression and the M2 phenotype. Overexpression of miR-99a prevented M1 phenotype activation and attenuated bactericidal activity. Likewise, knockdown of miR-99a abolished M2 phenotype activation. By means of in silico target prediction tools and a luciferase reporter assay, TNFα was identified as a direct target of miR-99a. Knockdown of TNFα recapitulated the effect of miR-99a overexpression in M1 BMDMs. In a db/db mice model, miR-99a expression was reduced in eWAT and F4/80 ATMs. Systemic overexpression of miR-99a in db/db mice attenuated adipocyte hypertrophy with increased CD301 and reduced CD86 immunostaining. Flow cytometry analysis also showed an increased M2 and a reduced M1 macrophage population. Mimics of miR-99a also improved the diabetic dyslipidemia and insulin signaling in eWAT and liver, with an attenuated expression of gluconeogenesis and cholesterol metabolism genes in the liver. Furthermore, adoptive transfer of miR-99a-overexpressing macrophages in the db/db mice recapitulated in vivo miR-99a mimic effects with increased M2 and reduced M1 macrophage populations and improved systemic glucose, insulin sensitivity, and insulin signaling in the eWAT and liver. The present study demonstrates that miR-99a mimics can regulate macrophage M1 phenotype activation by targeting TNFα. miR-99a therapeutics in diabetic mice reduces the adipose tissue inflammation and improves insulin sensitivity.

show abstract

“…Reduction of inflammatory gene expression by SP may be due to changes in the population of immune cells found in the spleen, which has been demonstrated to change in response to obesity (36,37) . Alternatively, components found in SP may also reduce inflammatory gene expression in splenocytes by inhibiting the Toll-like receptor 4 signalling pathways.…”

Section: Discussionmentioning

confidence: 99%

Spirulina supplementation in a mouse model of diet-induced liver fibrosis reduced the pro-inflammatory response of splenocytes

et al. 2019

View full text Add to dashboard Cite

Treatment of liver fibrosis is very limited as there is currently no effective anti-fibrotic therapy. Spirulina platensis (SP) is a blue-green alga that is widely supplemented in healthy foods. The objective of this study was to determine whether SP supplementation can prevent obesity-induced liver fibrosis in vivo. Male C57BL/6J mice were randomly assigned to a low-fat or a high-fat (HF)/high-sucrose/high-cholesterol diet or an HF diet supplemented with 2·5 % SP (w/w) (HF/SP) for 16 or 20 weeks. There were no significant differences in body weight, activity, energy expenditure, serum lipids or glucose tolerance between mice on HF and HF/SP diets. However, plasma alanine aminotransferase level was significantly reduced by SP at 16 weeks. Expression of fibrotic markers and trichrome stains showed no differences between HF and HF/SP. Splenocytes isolated from HF/SP fed mice had lower inflammatory gene expression and cytokine secretion compared with splenocytes from HF-fed mice. SP supplementation did not attenuate HF-induced liver fibrosis. However, the expression and secretion of inflammatory genes in splenocytes were significantly reduced by SP supplementation, demonstrating the anti-inflammatory effects of SP in vivo. Although SP did not show appreciable effect on the prevention of liver fibrosis in this mouse model, it may be beneficial for other inflammatory conditions.

show abstract

CD4+ T cells memorize obesity and promote weight regain

Cited by 50 publications

References 57 publications

White adipose tissue inflammation is not attenuated by short-term calorie restriction in obese humans

White adipose tissue inflammation is not attenuated by short-term calorie restriction in obese humans

MicroRNA-99a mimics inhibit M1 macrophage phenotype and adipose tissue inflammation by targeting TNFα

Spirulina supplementation in a mouse model of diet-induced liver fibrosis reduced the pro-inflammatory response of splenocytes

Contact Info

Product

Resources

About