Adipose tissue–resident T cells play vital roles in regulating inflammation and metabolism in obesity, but the underlying mechanisms remain unclear. Here, we show that high-fat diet (HFD) feeding enhances p38 activity in adipose-resident T cells. T cell–specific deletion of p38α, an essential subunit of p38 expressed in most immune cells, protected mice from HFD-induced obesity, hepatic steatosis, adipose tissue inflammation, and insulin resistance. Mice with p38α deletion in T cells exhibited higher energy expenditure. Mechanistically, p38α promoted T-cell glycolysis through mechanistic target of rapamycin signaling, leading to enhanced Th1 differentiation. Accordingly, genetic deletion of p38α alleviated ongoing diet-induced obesity. Unexpectedly, p38α signaling in T cells promoted adipose tissue senescence during obesity and aging. Taken together, our results identify p38α in T cells as an essential regulator of obesity, insulin resistance, and adipose tissue senescence, and p38α may be a therapeutic target for obese- or aging-associated diseases.

Obesity is a worldwide epidemic, leading to severe health complications, including insulin resistance, diabetes, fatty liver, and cardiovascular disease (1). Obesity alters both innate and adaptive immunity, resulting in chronic low-grade inflammation in adipose tissue and a systemic proinflammatory state, which contributes to insulin resistance and other metabolic abnormalities (2,3). Accumulating studies have shown that immune cells, such as T cells, B cells, macrophages, and dendritic cells (DCs), are actively involved in promoting adipose tissue inflammation and obesity (4). CD4+ T cells and CD8+ T cells in obese adipose tissue can directly drive inflammation and inhibit insulin signaling by secreting cytokines such as interferon-γ (IFN-γ) (57). Moreover, these proinflammatory mediators influence adipose tissue expansion and adipocyte differentiation (8). Regulatory T cells (Tregs), suppressing inflammation and maintaining a normal homeostatic metabolic environment, are inversely correlated with obesity (6,9). Although T cells are appreciated as the important regulator in the pathogenesis of obesity, the underlying molecular mechanisms remain incompletely understood.

Similar to obesity, aging is another global health issue, associated with abdominal obesity, insulin resistance, metabolic syndrome, and cardiovascular disease (10). With advancing age, individual organisms exhibit deteriorative changes and a decline in immune competence referred to as immunosenescence, which contributes to or is recognized to be partly driven by chronic low-grade inflammation (11). Immunologic and metabolic dysfunctions in adipose tissue influence animal longevity, suggesting an important role in the aging process (12). However, the role of adipose tissue immune cells, especially T cells, and their interplay with metabolic process in aging are poorly understood. Accumulating evidence suggests that obesity can accelerate the aging process (13), but the mechanism involved is still unclear.

The p38 mitogen-activated protein kinase (MAPK) signaling pathway plays prominent roles in a wide variety of cellular processes such as proliferation, differentiation, and metabolism (14), as well as in innate and adaptive immunity (15). p38 has been shown to play a critical role in glucose homeostasis. Activation of p38 MAPK by expression of constitutively active MAPKK6 establishes euglycemia in severely obese mice (16). In addition, p38 MAPK plays a stimulatory role in hepatic gluconeogenesis (17). Genetic ablation of hepatic p38α, one major form of p38 MAPK, increases simple steatosis but ameliorates oxidative stress–driven nonalcoholic fatty liver disease (18). Adipocytes lacking of p38α facilitate the browning in white adipose tissue and confer metabolic benefits (19). Moreover, MAPKs modulate many proteins involved in the main senescence-regulatory axes (20). According to previous studies, p38α plays various roles in different cells and diseases. However, the roles of p38α in different immune cell types in obesity and its role in aging remain to be explored.

In the current study, we examined the role of p38α in high-fat diet (HFD)-induced obesity (DIO) using mice with p38α-specific deletion in macrophages, DCs, and T cells and aimed to explore whether p38α represents an exciting pharmacologic target to combat obesity and metabolic diseases. We also explored a potential link between obesity and aging through p38α signaling.

Materials

Materials are listed in Supplementary Table 1.

Mice

Mapk14fl/fl, Rosa26-Cre-ERT2, and CD4-cre mice have been described previously (21,22). All mice were maintained in specific pathogen-free conditions in the Shanghai Jiao Tong University School of Medicine (SHSMU) according to SHSMU Institutional Animal Care and Use Committee–approved protocols. Crossbred Mapk14fl/fl and Rosa26-Cre-ERT2 mice are referred to as p38αcreER mice. Mice were fed with either normal fat diet (NFD) or HFD (60 kcal% fat; Research Diets D12492) generally from age 6 to 8 weeks for at least 16 weeks. In this study, cre;Mapk14fl/fl mice or CD4-cre+;Mapk14wt/wt mice were used as controls for the p38αΔT mice. Mice were weighed twice weekly. Overnight-fasted mice were used for tissue sample collection.

Glucose and Insulin Sensitivity

For glucose tolerance and insulin tolerance tests, mice were fasted for 16 and 4 h, respectively, and intraperitoneal injection of 1.5 g/kg d-glucose and 0.8 units/kg insulin was used for the respective tests. Glucose was measured from tail-vein blood with ONE-TOUCH UltraEasy glucometer and glucose test strips.

Energy Expenditure Measurement

After HFD for 16 weeks, mice were moved to the Oxymax/CLAMS system (Columbus Instruments) for 3 days to monitor energy balance. Energy expenditure was calculated, and physical activity was recorded.

Histology

Tissues were fixed in 4% formaldehyde (4°C overnight) embedded in paraffin. Histology was performed by the Wuhan Servicebio Technology Co. Slides were imaged at ×20 original magnification in the imaging core of SHSMU.

Flow Cytometry

Stromal vascular fraction of visceral epididymal white adipose tissue (eWAT) was isolated by collagenase digestion as described (23). For analysis of surface markers, cells were stained in PBS containing 2% FBS with antibodies as indicated. The Cytofix/Cytoperm Fixation/Permeabilization Solution Kit and Foxp3/Transcription Factor Staining Buffer Set Kit were used for determining cytokine expression and Foxp3 staining.

T-Cell Differentiation In Vitro

Sorted naive CD4+ T cells were stimulated with anti-CD3/CD28 (2 μg/mL), and irradiated splenocytes were used as antigen-presenting cells. Cultures were stimulated as follows: Th1 cultures, 3.5 ng/mL interleukin-12 (IL-12), 10 μg/mL anti–IL-4 antibody, and 20 ng/mL IL-2; Th2 cultures, 10 ng/mL IL-4, 10 μg/mL anti–IFN-γ antibody, and 20 ng/mL IL-2; Th17 cultures, 2.5 ng/mL transforming growth factor-β, 20 ng/mL IL-6, and 20 ng/mL IL-23; and induced Treg cultures, 5 ng/mL transforming growth factor-β and 20 ng/mL IL-2. Cell differentiation was analyzed by flow cytometry after 4–5 days. Naive CD8 T cells were activated with plate-bound anti-CD3/CD28 antibodies (2 μg/mL) for 48 h for analysis.

Western Blot Analysis

Cells were lysed with radioimmunoprecipitation assay buffer containing protease/phosphatase inhibitor and 1 mmol/L phenylmethylsulfonyl fluoride on ice for 30 min. Lysates were centrifuged, and supernatants were collected for analysis. Antibodies are listed in Supplementary Table 1.

Quantitative Real-Time PCR

RNA of tissues and cells was extracted using TRIzol. Real-time PCR was performed with SYBR dyes in the ViiA7 Real-Time PCR System. Relative mRNA levels were normalized to Hprt. Primer sequences are listed in Supplementary Table 2.

Fasting Blood Glucose, Insulin, and Cytokines

Glucose was measured from tail-vein blood from overnight-fasted mice. Plasma and tissue were stored for insulin and cytokine measurement by ELISA.

Glycolytic and Mitochondrial Respiration Rate Measurement

Naive CD4 T cells was stimulated with anti-CD3/CD28 antibodies for 24 h. The Seahorse XFe96 Extracelluar Flux Analyzer (Agilent Technologies) was used for cell metabolic experiments according to protocols of the Seahorse XF Glycolysis Stress Test Kit and Cell Mito Stress Test Kit.

Statistics

Statistical analysis was performed with GraphPad Prism 6, and values are presented as mean ± SD. Student t test and two-way ANOVA with Bonferroni posttest were used for comparisons (*P < 0.05, **P < 0.01, ***P < 0.001).

Data and Resource Availability

The data sets analyzed during the current study are available from the corresponding author on reasonable request.

Deletion of p38α in T Cells Ameliorates DIO

Inflammation is a common characteristic of DIO, and p38 MAPK is essential for inflammation regulation (15,24). To investigate the role of p38 in DIO, we fed wild-type (WT) mice with HFD. The activation of p38 (phospho Thr180/Tyr182-p38 [p-p38]) in the eWAT was upregulated (Fig. 1A and Supplementary Fig. 1A), indicating that p38 might play an important role in DIO. p38α (encoded by Mapk14) is an essentially dominant subunit of p38, and Makp14 was highly expressed in the muscle, eWAT, spleen, and thymus, as well as in immune cells such as T and B cells (Supplementary Fig. 1B). To further analyze the role of p38α in obesity, WT and p38αcreER mice were treated with tamoxifen to delete p38α ubiquitously, and the mice were then fed HFD. Expectedly, p38α was efficiently deleted in the splenic CD4+ T cells, eWAT, and liver of p38αcreER mice, but this did not occur in WT mice (Supplementary Fig. 1C). Compared with WT mice, p38αcreER mice gained less body weight (Fig. 1B) and eWAT mass (Fig. 1C). p38αcreER mice showed improved glucose tolerance but comparable insulin sensitivity compared with WT mice (Fig. 1D and E). In addition, p38αcreER mice had smaller adipocytes in the eWAT, fewer lipid droplets in the liver, and smaller multilocular adipocytes in the brown adipose tissue (BAT) than WT mice (Fig. 1F and G). Immumohistochemical staining showed less macrophage accumulation in the eWAT in p38αcreER mice (Fig. 1H). Flow cytometry revealed modest increase in anti-inflammatory Foxp3+ Tregs and IL-4+ CD4+ T cells in p38αcreER mice, whereas IL-17+ and IFN-γ+ CD4+ T cells were comparable (Supplementary Fig. 1D and E). The expression of certain inflammatory cytokines such as IFN-γ, IL-1β, tumor necrosis factor-α (TNF-α), and IL-6 in the adipose tissue, liver, and circulation was also comparable between WT and p38αcreER mice upon HFD treatment (Supplementary Fig. 1F).

Figure 1

p38α in T cells is necessary for DIO. A: Immunofluorescence of p-p38 in the eWAT of mice fed with NFD or HFD for 4 weeks. Quantification of p-p38 IOD change relative to DAPI. p-p38, red; DAPI, blue. BH: WT and p38αcreER male mice were fed with HFD for 28 weeks after intraperitoneal injection of tamoxifen. Body weight before and after HFD feeding (B), eWAT mass (C), glucose tolerance test (GTT) (D), insulin tolerance test (ITT) (E), representative hematoxylin-eosin (H&E) staining of liver, eWAT, and BAT sections (scale bars 100 μm) (F), quantitative analysis of adipocyte cell diameter from eWAT and multilocular area of brown adipocytes from BAT (G), and immunohistochemistry (IHC) of F4/80 in eWAT (scale bars 100 μm) (H) at 26 weeks of HFD (n = 4–6). I: Flow cytometric analysis of p-p38 in CD4+ T cells in the eWAT of mice fed with NFD or HFD for 20 weeks. JM: WT and p38αΔT male mice were fed with HFD for 16 weeks. Body weight (J), GTT (K), and ITT (L) were performed at 15 weeks (n = 5–6); serum insulin and fasting blood glucose levels (M) were measured by ELISA at 16 weeks (n = 7–9). Data are representative of two (AI) or three (JM) independent experiments. Data are presented as mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001. AUC, area under the curve; IOD, integrated optical density; ns, not significant.

Figure 1

p38α in T cells is necessary for DIO. A: Immunofluorescence of p-p38 in the eWAT of mice fed with NFD or HFD for 4 weeks. Quantification of p-p38 IOD change relative to DAPI. p-p38, red; DAPI, blue. BH: WT and p38αcreER male mice were fed with HFD for 28 weeks after intraperitoneal injection of tamoxifen. Body weight before and after HFD feeding (B), eWAT mass (C), glucose tolerance test (GTT) (D), insulin tolerance test (ITT) (E), representative hematoxylin-eosin (H&E) staining of liver, eWAT, and BAT sections (scale bars 100 μm) (F), quantitative analysis of adipocyte cell diameter from eWAT and multilocular area of brown adipocytes from BAT (G), and immunohistochemistry (IHC) of F4/80 in eWAT (scale bars 100 μm) (H) at 26 weeks of HFD (n = 4–6). I: Flow cytometric analysis of p-p38 in CD4+ T cells in the eWAT of mice fed with NFD or HFD for 20 weeks. JM: WT and p38αΔT male mice were fed with HFD for 16 weeks. Body weight (J), GTT (K), and ITT (L) were performed at 15 weeks (n = 5–6); serum insulin and fasting blood glucose levels (M) were measured by ELISA at 16 weeks (n = 7–9). Data are representative of two (AI) or three (JM) independent experiments. Data are presented as mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001. AUC, area under the curve; IOD, integrated optical density; ns, not significant.

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The increased p38 activity could be detected in eWAT-associated CD4+ T cells, CD8 T cells, B cells, and CD11c+MHC-II+ cells, especially in CD4+ T cells (Fig. 1I and Supplementary Fig. 1G). T cells have been shown to play an important role in regulating adipose tissue inflammation in obesity (5,6). To further assess the potential contributions of p38α signaling in T cells to DIO in vivo, we obtained mice with p38α-specific deletion in T cells by crossing p38αflox/flox mice with CD4-cre mice (here referred to as p38αΔT mice). CD4-cre is turned on from the late CD4/CD8 double-negative stage and fully expressed at the CD4/CD8 double-positive stages, leading to the deletion of floxed sequences in both CD4 and CD8 T cells (25). p38α deletion in T cells was confirmed by Western blot analysis (Supplementary Fig. 2A). Although p38α deletion in T cells did not affect T-cell development in the thymus, spleen, or peripheral blood, B- or NK-cell development in the spleen, or T-cell subsets in the spleen (Supplementary Fig. 2BE), this deletion rendered mice with a defective response to Listeria monocytogenes infection (Supplementary Fig. 2F). These results suggest that p38α signaling is important for T-cell function. Notably, p38αΔT mice had comparable blood glucose and weight gain to Rag1−/− mice (Supplementary Fig. 2G).

To examine the role of p38α in T cells in DIO, we fed WT and p38αΔT mice with HFD. p38αΔT mice gained less body weight and had improved glucose tolerance and insulin sensitivity compared with WT mice (Fig. 1J–L), along with decreased fasting serum insulin and glucose (Fig. 1M). Notably, body weight, eWAT mass, cell infiltration, glucose tolerance, and insulin sensitivity were similar in p38αΔT and WT mice fed with NFD (Supplementary Fig. 3AD). Given that macrophages and DCs have been shown to be involved in the development of DIO, we next examined the cellular targets for p38α in obesity by using mice with p38α-specific deletion in macrophages (p38αΔM) and DCs (p38αΔDC). Our results revealed that both p38αΔM and p38αΔDC mice had comparable weight gain to WT mice (Supplementary Figs. 4A and 5A). Further analysis indicated no significant difference in liver or eWAT mass, glucose tolerance, insulin sensitivity, or cell infiltration in the eWAT between p38αΔM and WT mice (Supplementary Fig. 4BF). Similar results were observed between p38αΔDC and WT mice (Supplementary Fig. 5BF). Together, these findings suggest that p38α deficiency in T cells, but not in macrophages or DCs, ameliorates DIO, glucose tolerance, and insulin resistance.

p38α in T Cells Promotes Adipose Tissue Inflammation During DIO

The above results prompted us to explore whether p38α in T cells could promote eWAT inflammation upon HFD treatment. We first observed that p38αΔT mice had a significant reduction in eWAT mass compared with WT mice (Fig. 2A). In addition, p38αΔT mice had less cell infiltration in the eWAT, smaller adipocyte size in the eWAT and inguinal adipose tissue, and smaller multilocular adipocytes in the BAT compared with WT mice (Fig. 2B). The lower macrophage accumulation in the eWAT of p38αΔT mice was further confirmed by immunohistochemical staining (Fig. 2C). To investigate the cellular mechanisms for p38α-dependent T cell–driven adipose tissue inflammation, we assessed T cells and their cytokine profiles in the eWAT of mice with DIO. The percentage and number of CD4+ T cells, but not CD8+ T cells, were largely reduced in p38αΔT mice compared with WT mice (Fig. 2D). Although there was a modestly higher percentage of IL-4 in CD4+ T cells (Fig. 2E), p38αΔT mice had lower numbers of IFN-γ+ and TNF-α+ cells in both CD4+ and CD8+ T cells in the eWAT than WT mice (Fig. 2F). Real-time PCR analysis revealed that p38αΔT mice had increased expression of Adipoq and reduced expression of Ifng, Ccl5, and Ccl2 in the eWAT than WT mice (Fig. 2G). ELISA further confirmed a reduced IFN-γ level in the eWAT and serum of p38αΔT mice, whereas other cytokines such as IL-1β and IL-6 were comparable between WT and p38αΔT mice (Fig. 2H). Thus, p38α in T cells promotes adipose tissue inflammation upon HFD treatment. Although Tregs play a critical role in adipose tissue (6,9), our results showed that p38α was not required for Treg subset development or Treg function in DIO (Supplementary Fig. 6AG).

Figure 2

p38α in T cells promotes adipose tissue inflammation. WT and p38αΔT male mice were fed with HFD for 16 weeks. A: eWAT mass was measured. B: Representative H&E staining of eWAT, inguinal white adipose tissue (iWAT), and BAT sections (scale bars 100 μm). C: Immunohistochemistry of F4/80 in eWAT (scale bars 100 μm) (F4/80 is in brown) (left); number of crown-like structures was quantified (right). D: Quantification of CD4+ and CD8+ T-cell percentages and cell numbers in eWAT. E: Flow cytometric analysis of T-cell subset percentages in the eWAT of obese WT and p38αΔT male mice. F: Cell numbers of Th1, Th2, Th17, Treg, and TNF-α+ CD4+ and CD8+ T cells and IFN-γ+ CD8+ T cells in eWAT. G: Real-time PCR analysis of mRNA expression of indicated genes (normalized with Hprt) in eWAT. H: IFN-γ, IL-1β, IL-6, and TNF-α levels in the serum and eWAT homogenates of obese WT and p38αΔT male mice were measured by ELISA. Data are representative of two (CH) or three (A and B) independent experiments with four to six mice per group. Data are presented as mean ± SD. *P < 0.05; **P < 0.01. CLS, crown-like structures; N/A, not applicable; ns, not significant.

Figure 2

p38α in T cells promotes adipose tissue inflammation. WT and p38αΔT male mice were fed with HFD for 16 weeks. A: eWAT mass was measured. B: Representative H&E staining of eWAT, inguinal white adipose tissue (iWAT), and BAT sections (scale bars 100 μm). C: Immunohistochemistry of F4/80 in eWAT (scale bars 100 μm) (F4/80 is in brown) (left); number of crown-like structures was quantified (right). D: Quantification of CD4+ and CD8+ T-cell percentages and cell numbers in eWAT. E: Flow cytometric analysis of T-cell subset percentages in the eWAT of obese WT and p38αΔT male mice. F: Cell numbers of Th1, Th2, Th17, Treg, and TNF-α+ CD4+ and CD8+ T cells and IFN-γ+ CD8+ T cells in eWAT. G: Real-time PCR analysis of mRNA expression of indicated genes (normalized with Hprt) in eWAT. H: IFN-γ, IL-1β, IL-6, and TNF-α levels in the serum and eWAT homogenates of obese WT and p38αΔT male mice were measured by ELISA. Data are representative of two (CH) or three (A and B) independent experiments with four to six mice per group. Data are presented as mean ± SD. *P < 0.05; **P < 0.01. CLS, crown-like structures; N/A, not applicable; ns, not significant.

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Deletion of p38α in T Cells Alleviates Liver Steatosis Upon HFD Treatment

Given that DIO promotes lipid metabolic dysfunction, inflammation, and immune cell accumulation in the liver, we next explored lipid deposition and leukocyte profiling in the liver. Compared with WT mice, p38αΔT mice had smaller liver mass (Fig. 3A) and reduced lipid droplets and triglyceride content (Fig. 3B–D). Although certain inflammatory cytokines such as IFN-γ, TNF-α, IL-1β, and IL-6 and myeloid cells such as Kupffer cells, macrophages, monocytes, neutrophils, and eosinophils did not show much difference in the liver of WT and p38αΔT mice, we observed reduced accumulation of IFN-γ+ T cells in p38αΔT mice compared with WT mice (Supplementary Fig. 7AC). We also measured the expression pattern of genes in the liver from the overnight-fasted mice. We found that p38αΔT mice had increased expression of certain genes related to gluconeogenesis, such as G6pase, Pepck, and Foxo1, but not Fbp1 or Pcx, compared with WT mice (Fig. 3E). WT and p38αΔT mice had comparable expression of genes involved in glycolysis (Hk2, Tpi, Eno1, Pkm, and Ldha), fatty acid synthesis (Fasn, Acc1, Scd1, and Scd2), and oxidation (Cpt1a, Cpt2, Acsl1, and Acsl3) (Fig. 3E and F). Together, these data suggest that p38α signaling in T cells promotes liver steatosis upon HFD treatment.

Figure 3

p38α in T cells promotes liver lipid deposition. WT and p38αΔT male mice were fed with HFD for 16 weeks. A: Liver mass was measured. B: Representative H&E staining of liver sections. C: Representative oil red O staining of liver sections (scale bars 100 μm). D: The content of triglyceride in the liver was measured. E and F: Real-time PCR analysis of mRNA expression of gluconeogenesis and glycolysis-related genes (E) and fatty acid synthesis and oxidation-related genes (F) (normalized with Hprt) in overnight-fasted liver (n = 3–4). Data are representative of three independent experiments with three to four mice per group. Data are presented as mean ± SD. *P < 0.05, **P < 0.01. ns, not significant.

Figure 3

p38α in T cells promotes liver lipid deposition. WT and p38αΔT male mice were fed with HFD for 16 weeks. A: Liver mass was measured. B: Representative H&E staining of liver sections. C: Representative oil red O staining of liver sections (scale bars 100 μm). D: The content of triglyceride in the liver was measured. E and F: Real-time PCR analysis of mRNA expression of gluconeogenesis and glycolysis-related genes (E) and fatty acid synthesis and oxidation-related genes (F) (normalized with Hprt) in overnight-fasted liver (n = 3–4). Data are representative of three independent experiments with three to four mice per group. Data are presented as mean ± SD. *P < 0.05, **P < 0.01. ns, not significant.

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p38α Deficiency in T Cells Increases Mouse Energy Expenditure

To investigate this major driver in the development of obesity, mouse metabolic cage analyses were performed. WT and p38αΔT mice had comparable oxygen consumption, carbon dioxide production, energy expenditure, and respiratory exchange ratio under NFD feeding (Supplementary Fig. 8AD). However, upon HFD feeding, p38αΔT mice exhibited significantly higher oxygen consumption, carbon dioxide production, and energy expenditure than WT mice (Fig. 4A–C). We also observed higher respiratory exchange ratio value from HFD-fed p38αΔT mice during the night (Fig. 4D), indicating a lower use of fat as energy source. These results indicate that p38α deficiency in T cells increases mouse energy expenditure.

Figure 4

p38α deficiency in T cells increases energy expenditure. WT and p38αΔT male mice were fed with HFD for 16 weeks. AD: Metabolic cage analyses were performed to measure oxygen (O2) consumption (A), carbon dioxide (CO2) production (B), energy expenditure (C), and respiratory exchange ratio (RER) (D). Data are representative of two independent experiments with four mice per group. Data are presented as mean ± SD. *P < 0.05, **P < 0.01. ns, not significant.

Figure 4

p38α deficiency in T cells increases energy expenditure. WT and p38αΔT male mice were fed with HFD for 16 weeks. AD: Metabolic cage analyses were performed to measure oxygen (O2) consumption (A), carbon dioxide (CO2) production (B), energy expenditure (C), and respiratory exchange ratio (RER) (D). Data are representative of two independent experiments with four mice per group. Data are presented as mean ± SD. *P < 0.05, **P < 0.01. ns, not significant.

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p38α Signaling Promotes Th1 Differentiation In Vitro

To explore the potential molecular mechanism of p38α signaling in T cells in driving eWAT inflammation, we performed RNA sequencing using CD4+ T cells isolated from the eWAT after 5 weeks of HFD feeding. We found that p38α-deficient CD4+ T cells had largely downregulated pathways of leukocyte activation and T-cell receptor signaling, along with dramatic reduction of IFN-γ and IL-2 expression, compared with WT T cells (Fig. 5A). These results were further confirmed by real-time PCR analysis of splenic CD4+ T cells isolated from obese mice (Fig. 5B). p38αΔT T cells had less competence to differentiate into IFN-γ+ Th1 cells, but comparable Th2 and Th17 cells and induced Tregs, in vitro (Fig. 5C). Furthermore, p38αΔT CD8+ T cells had decreased production of functional factors compared with WT CD8+ T cells (Fig. 5D). Collectively, these results demonstrate that p38α signaling in T cells promotes Th1 differentiation in vitro.

Figure 5

p38α deficiency decreases Th1 polarization. A: Heat map of downregulated genes associated with T-cell activation and cytokines in p38αΔT CD4+ T cells relative to those in WT CD4+ T cells from the eWAT of mice fed with HFD for 5 weeks. B: Real-time PCR analysis of indicated gene expression in splenic CD4+ T cells from WT and p38αΔT male mice fed with HFD for 16 weeks. C: Expression of IFN-γ, IL-4, IL-17A, and Foxp3 in CD4+ T cells cultured under Th1, Th2, Th17, and iTreg conditions, respectively. D: Expression of CD8+ T-cell functional cytokines in naive WT and p38αΔT CD8+ T cells stimulated with anti-CD3 and anti-CD28 antibodies for 2 days. Data are from one experiment (A and B) or pooled from three or four independent experiments (C and D). Data are presented as mean ± SD. *P < 0.05, ***P < 0.001. MFI, mean fluorescence intensity; ns, not significant.

Figure 5

p38α deficiency decreases Th1 polarization. A: Heat map of downregulated genes associated with T-cell activation and cytokines in p38αΔT CD4+ T cells relative to those in WT CD4+ T cells from the eWAT of mice fed with HFD for 5 weeks. B: Real-time PCR analysis of indicated gene expression in splenic CD4+ T cells from WT and p38αΔT male mice fed with HFD for 16 weeks. C: Expression of IFN-γ, IL-4, IL-17A, and Foxp3 in CD4+ T cells cultured under Th1, Th2, Th17, and iTreg conditions, respectively. D: Expression of CD8+ T-cell functional cytokines in naive WT and p38αΔT CD8+ T cells stimulated with anti-CD3 and anti-CD28 antibodies for 2 days. Data are from one experiment (A and B) or pooled from three or four independent experiments (C and D). Data are presented as mean ± SD. *P < 0.05, ***P < 0.001. MFI, mean fluorescence intensity; ns, not significant.

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p38α Signaling Promotes CD4+ T-Cell Glycolysis and Mechanistic Target of Rapamycin Signaling

T cells rely on aerobic glycolysis to maintain the energy requirements and material needs of proliferation and differentiation (26). p38αΔT CD4+ T cells had significantly lower baseline and maximum glycolytic rates than WT CD4+ T cells (Fig. 6A), indicating that p38α is involved in CD4+ T-cell glycolysis. However, WT and p38αΔT CD4+ T cells had comparable baseline and maximum oxidative phosphorylation rates (Fig. 6B). Furthermore, WT and p38αΔT CD4+ T cells had comparable mitochondrial mass and mitochondrial membrane potential (Fig. 6C), suggesting that p38α is dispensable for CD4+ T-cell mitochondrial fitness. Next, we determined whether the reduced glycolysis contributed to the decreased Th1 differentiation in p38αΔT CD4+ T cells. Inhibition of glycolysis with 2-deoxy-d-glucose had a strong effect on the diminished Th1 differentiation in a dose-dependent manner and led to comparable Th1 differentiation between WT and p38αΔT CD4+ T cells (Fig. 6D). The mechanistic target of rapamycin (mTOR) signaling pathway is well known to regulate T-cell glycolysis and IFN-γ production (2729). We examined the activity of mTORC1 (by measuring the phosphorylation of S6K1 and S6), and the results revealed reduced mTORC1 activity in p38αΔT CD4+ T cells activated by anti-CD3 and anti-CD28 stimulation (Fig. 6E). Moreover, p38αΔT CD4+ T cells had less phosphorylation of AKT at Ser473 and Foxo1 than WT CD4+ T cells, indicating reduced mTORC2 activity. However, p38αΔT CD4+ T cells had normal PI3K activity (by measuring the phosphorylation of AKT at Thr308) compared with WT CD4+ T cells (Fig. 6E). In addition, we examined the expression of the mTOR negative regulator PTEN and found that PTEN was increased in p38αΔT CD4+ T cells compared with WT CD4+ T cells (Fig. 6F). Because mTORC1 activates the synthesis of c-Myc, a crucial transcription factor for T-cell glycolysis, we also observed lower expression of c-Myc in p38αΔT CD4+ T cells compared with WT CD4+ T cells (Fig. 6F). The phosphorylation of AMPK, a regulator of mTOR, and MK2, a target of p38α, was comparable in p38αΔT CD4+ T cells and WT CD4+ T cells (Fig. 6F). Taken together, these findings demonstrate that p38α is required for mTOR signaling activation and glycolytic reprogramming, which further determine the fate of Th1 differentiation.

Figure 6

p38α in CD4+ T cells promotes glycolysis and mTOR signaling. A: Extracellular acidification rate (ECAR) of naive WT and p38αΔT CD4+ T cells stimulated with anti-CD3 and anti-CD28 antibodies for 24 h. B: Extracellular flux analysis of the oxygen consumption rate (OCR) of naive WT and p38αΔT CD4+ T cells stimulated with anti-CD3 and anti-CD28 antibodies for 24 h. C: Flow cytometric analysis of MitoTracker, tetramethylrhodamine (TMRM), and reactive oxygen species (ROS) staining in naive WT and p38αΔT CD4+ T cells stimulated with anti-CD3 and anti-CD28 for 24 h. D: Expression of IFN-γ in CD4+ T cells cultured under Th1 conditions with 0, 1, or 2 mmol/L 2-deoxy-d-glucose (2-DG). E and F: Western blot analysis of indicated proteins in naive WT and p38αΔT CD4+ T cells stimulated as indicated. Data are pooled from three (A and B) or representative of two independent experiments (CF). Data are presented as mean ± SD. *P < 0.05. MFI, mean fluorescence intensity; ns, not significant.

Figure 6

p38α in CD4+ T cells promotes glycolysis and mTOR signaling. A: Extracellular acidification rate (ECAR) of naive WT and p38αΔT CD4+ T cells stimulated with anti-CD3 and anti-CD28 antibodies for 24 h. B: Extracellular flux analysis of the oxygen consumption rate (OCR) of naive WT and p38αΔT CD4+ T cells stimulated with anti-CD3 and anti-CD28 antibodies for 24 h. C: Flow cytometric analysis of MitoTracker, tetramethylrhodamine (TMRM), and reactive oxygen species (ROS) staining in naive WT and p38αΔT CD4+ T cells stimulated with anti-CD3 and anti-CD28 for 24 h. D: Expression of IFN-γ in CD4+ T cells cultured under Th1 conditions with 0, 1, or 2 mmol/L 2-deoxy-d-glucose (2-DG). E and F: Western blot analysis of indicated proteins in naive WT and p38αΔT CD4+ T cells stimulated as indicated. Data are pooled from three (A and B) or representative of two independent experiments (CF). Data are presented as mean ± SD. *P < 0.05. MFI, mean fluorescence intensity; ns, not significant.

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Acute Deletion of p38α Ameliorates Ongoing DIO

The above results prompted us to examine whether acute deletion of p38α could alleviate the ongoing obesity induced by HFD treatment. WT and p38αcreER mice were intraperitoneally injected with tamoxifen to induce p38α deletion after 5 weeks of HFD feeding. We found that p38αcreER mice gained less weight (Fig. 7A), accompanied by lower eWAT mass and cell infiltration, than WT mice (Fig. 7B). Moreover, p38αcreER mice had improved glucose tolerance compared with WT mice (Fig. 7C). However, insulin sensitivity was similar in p38αcreER mice and WT mice (Fig. 7D). By using Rag1−/− mice fed with HFD in the presence or absence of a p38α inhibitor (SB203580), our results showed that p38α in other tissues or cells also played an important role in HFD-induced obesity and insulin resistance (Supplementary Fig. 9AG).

Figure 7

Acute deletion of p38α is a potential therapeutic strategy for DIO. WT and p38αcreER male mice were injected with tamoxifen after HFD feeding for 5 weeks and continued with HFD feeding for 14 weeks. AD: Body weight and body weight gain percentage (A), eWAT mass and cell infiltration (B), glucose tolerance test (GTT) (C) and insulin tolerance test (ITT) (D). Data are representative of two independent experiments with five mice per group. Data are presented as mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001. AUC, area under the curve; SVF, stromal vascular fraction.

Figure 7

Acute deletion of p38α is a potential therapeutic strategy for DIO. WT and p38αcreER male mice were injected with tamoxifen after HFD feeding for 5 weeks and continued with HFD feeding for 14 weeks. AD: Body weight and body weight gain percentage (A), eWAT mass and cell infiltration (B), glucose tolerance test (GTT) (C) and insulin tolerance test (ITT) (D). Data are representative of two independent experiments with five mice per group. Data are presented as mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001. AUC, area under the curve; SVF, stromal vascular fraction.

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p38α Enhances Adipose Tissue Senescence During Obesity and Aging

Recent studies have shown that obesity may accelerate the aging process (13). To examine whether p38α signaling in T cells is involved in obesity-driven aging process, we analyzed β-galactosidase expression (the readout for cellular senescence) in the eWAT of HFD-treated WT and p38αΔT mice. We found that HFD-fed obese p38αΔT mice (age 6 months) had lower β-galactosidase expression in the eWAT than WT mice (Fig. 8A). Real-time PCR analysis revealed that HFD-fed obese p38αΔT mice had lower expression of senescence-associated genes, such as p19arf, p21, and Igfbp5, in the eWAT than WT mice (Fig. 8B). We then analyzed whether p38α signaling in T cells directly affects the aging process. Aged p38αΔT mice had reduced IFN-γ, but comparable IL-4 and Foxp3 expression, in the splenic CD4+ T cells than WT littermate mice (Fig. 8C). Moreover, aged p38αΔT mice had lower β-galactosidase expression in the eWAT than WT littermate mice (Fig. 8D). These findings indicate that p38α signaling in T cells promotes adipose tissue senescence during obesity and aging.

Figure 8

p38α promotes adipose tissue senescence during obesity and aging. A: Senescence-associated β-galactosidase (SA-β-gal) staining of the eWAT of HFD-fed obese WT and p38αΔT male mice. B: Real-time PCR analysis of senescence-related gene expression in HFD-fed obese WT and p38αΔT male mice. C: Expression of IFN-γ, IL-4, and Foxp3 in CD4+ T cells in 8-month-old WT and p38αΔT mice. D: SA-β-gal staining of the eWAT of 10-month-old WT and p38αΔT mice. Scale bars 50 μm. Data are representative of two independent experiments with three to five mice per group. Data are presented as mean ± SD. *P < 0.05, **P < 0.01. ns, not significant.

Figure 8

p38α promotes adipose tissue senescence during obesity and aging. A: Senescence-associated β-galactosidase (SA-β-gal) staining of the eWAT of HFD-fed obese WT and p38αΔT male mice. B: Real-time PCR analysis of senescence-related gene expression in HFD-fed obese WT and p38αΔT male mice. C: Expression of IFN-γ, IL-4, and Foxp3 in CD4+ T cells in 8-month-old WT and p38αΔT mice. D: SA-β-gal staining of the eWAT of 10-month-old WT and p38αΔT mice. Scale bars 50 μm. Data are representative of two independent experiments with three to five mice per group. Data are presented as mean ± SD. *P < 0.05, **P < 0.01. ns, not significant.

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Obesity and aging are characterized by impaired immune function, leading to low-grade chronic inflammation (11). T cells are one of the main immune cell types in adipose tissue driving this chronic inflammation during aging and obesity (11,30), but the molecular signaling pathways mediating their functions remain largely unexplored. Here, we identified p38α as an important mediator of T cell–driven inflammation in adipose tissue of DIO, as well as adipose tissue senescence in both obesity and aging. Our findings link p38α signaling in T cells with immunity, metabolism, and aging.

It is well known that the immune dysfunction in adipose tissue is a main contributor to chronic inflammation during obesity and aging (11). Diet-induced adipose tissue expansion results in increased local hypoxia, disorder of fatty acid metabolism, adipocyte cell death, and increased chemokine secretion, which promote inflammatory cell infiltration and local inflammatory environment, leading to insulin resistance (10,24,31). However, the main changes during the aging process are the redistribution of adipose tissue, fat accumulation, accumulation of senescent cells, and changes in the function of fat precursor cells, leading to increased chronic inflammation (32). Exploring the potential mechanisms driving the chronic inflammation in aging and obesity processes is an active field. While a large number of studies focus on Tregs, there are few findings on effector T cells. Interestingly, effector T cells are significantly elevated in adipose tissue in both obese and aged mice, and these T cells produce high levels of inflammatory molecules such as IFN-γ to promote adipose tissue inflammation and insulin resistance (5,10,30,33). It has been reported that circulating T cells are activated in response to a metabolically driven adaptation via PI3K signaling in obesity (34). However, the molecular mechanism of these effector T cells mediating their profiles in response to the aging and obese eWAT environments remains largely unexplored. In the current study, we found that p38α signaling is vital for T cells to mediate chronic inflammation during both obesity and aging, filling the gap between these two processes.

Previous studies have reported that hepatic expression of Pepck and G6pase mRNA is not related to fasting hyperglycemia (35), and only hepatic pyruvate carboxylase protein levels are strongly associated with glycemia and insulin resistance (36). Although p38αΔT mice had fewer metabolic abnormalities, these mice had decreased fasting insulin and glucose in circulation, which might have direct or indirect effects on the transcriptional upregulation of G6pase, Pepck, and Foxo1 (genes involved in gluconeogenesis), or other mechanisms might be involved.

mTOR signaling modulates T-cell differentiation by integrating the signals of nutrients and cell growth–related factors and modulating metabolic reprogramming (28,37). Th1 differentiation depends on Rheb-mTORC1– and Rictor-mTORC2–mediated glycolysis (38,39). mTORC1 phosphorylates T-bet, the master transcription factor for Th1 cells, to improve Th1 differentiation (40). However, the signaling pathways involved in driving mTOR activation and Th1 differentiation are still not clear. We identified p38α as a positive regulator of CD4+ T-cell metabolic and differentiated fitness, and mTOR signaling is a key downstream effector linking p38α activity to increased glycolysis. At the molecular level, p38α might activate mTOR through downregulating PTEN expression. p38α deficiency impaired CD4+ T-cell glycolysis, mTOR activity, and Th1 differentiation. The inhibition of glycolysis with 2-deoxy-d-glucose largely reversed the Th1 differentiation defect in p38α-deficient T cells.

Age-related changes in fat distribution and metabolism are key factors in accelerating the aging process and triggering age-related diseases, which are exacerbated by obesity (41). DIO accelerates T-cell senescence in murine visceral adipose tissue (42). A large number of clinical observations have found that obesity further aggravates the occurrence of many age-related diseases and aging (43). Our study has uncovered an essential role of p38α signaling in T cells in promoting adipose tissue senescence induced by obesity, as well as in the aging process. The mechanism is worthy of further study.

Cell type–specific roles of p38α signaling in the pathogenesis of colitis have been reported (44,45). While p38α signaling in both macrophages and DCs is dispensable for DIO, T cells rely on this signaling to promote DIO. Although whole-body deletion of p38α signaling leads to decreased DIO, there are still certain phenotypes, such as ITT and proinflammatory cytokines in the eWAT, that remain different from the results of p38α-specific deletion in T cells, indicating that p38α in other cell types or tissues has different contributions. Indeed, by using Rag1−/− mice, we further distinguished the specific role of p38α in T cells and other tissues in the context of HFD-induced obesity and insulin resistance. Matesanz et al. (46) reported that the decreased p38α mRNA level in human visceral fat is correlated with higher BMI, and p38α could block BAT thermogenesis. Decreased p38α activity in inguinal and axillary (not in eWAT) fat depots from HFD or ob/ob mice or from preadipocytes to adipocytes has also been reported, and p38α has been shown to play a negative role in adipogenesis in this study (47). The differences in these studies, including experimental design, transcriptional or protein assay of p38α, and cell type, highlight the complex function of p38α in vivo. During the last decades, p38 has been a ubiquitous target in the research-based pharmaceutical industry, with small-molecule inhibitors for several clinical applications, including rheumatoid arthritis, pulmonary diseases, cancer, and Alzheimer disease (48). Our study demonstrates that targeting p38α in T cells may be a useful goal for treating dietary obesity and insulin resistance.

This article contains supplementary material online at https://doi.org/10.2337/figshare.19404491.

Acknowledgments. The authors thank H. Wang, J. Chen, B. Su, and B. Li (Shanghai Jiao Tong University School of Medicine, Shanghai, China) for providing CD4-cre mice, LysM-cre mice, Rosa26-Cre-ERT2 mice, and Rag1−/− mice, respectively.

Funding. This work was supported by grants 31670897, 91642104, and 81471528 (G.H.) and 82001702 (T.Z.) from the National Natural Science Foundation of China, 2018YFC0115900 (G.H.) from the National Key R&D Program of China, and CH/11/3/29051 (K.O.) from the British Heart Foundation.

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

Author Contributions. D.M., B.Z., Ya.W., T.Z., R.H., and B.W. performed the experiments. D.M. and G.H. conceived the experiments, analyzed data, and wrote the manuscript. Ya.W. edited the manuscript. K.O. provided Mapk14fl/fl mice. Yi.W. contributed reagents. G.H. provided overall direction. D.M. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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