CD4+ T cells memorize obesity and promote weight regain

Abstract

Body weight regain often causes failure of obesity therapies while the underlying mechanism remains largely unknown. In this study, we report that immune cells, especially CD4+ T cells, mediate the 'memory' of previous obese status. In a weight gain-loss-regain model, we found that C57BL/6J mice with an obesity history showed a much faster rate of body weight regain. This obesity memory could last for at least 2 months after previously obese mice were kept at the same body weight as non-obese mice. Surprisingly, such obesity memory was abrogated by dexamethasone treatment, whereas immunodeficient Rag1-/- and H2A-/- mice failed to establish such memory. Rag1-/- mice repossessed the obesity memory when immune cells or CD4+ T cells isolated from previously obese mice were transferred. Furthermore, depletion of CD4+ T cells led to obesity memory ablation. Taken together, we conclude that CD4+ T cells mediate obesity memory and promote weight regain.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1

Weight gain-loss-regain model and long-term obesity memory. The DIO model in C57BL/6J mice was established as per the simulative graph and timeline (a). Body weight curves (b–d) and body weight increment ratios during the weight regain period (e–g) were recorded to display obesity memory. Weight regain was induced with a HFD (b, e and d, g) and a RD (d, f). The data are shown as means±s.d. *P<0.05 and **P<0.01, unpaired Student’s t-test. §§§P<0.001, two-way ANOVA followed by the Bonferroni post hoc test. CTR, control group; DIO, diet-induced-obesity; HFD, high fat diet; MOH, obesity history group; RD, regular diet.

Figure 2

Metabolic parameters of C57BL/6J mice before weight regain. Body weight (a), body length (b), overall and local bone mineral density (c), bone mineral content, lean mass and fat mass (d) and body fat percentage (e) values were measured to determine body compositions, especially fat content, of the MOH and CTR mice. The fasting and postprandial blood glucose levels (f) and insulin sensitivity (g) were detected to determine glucose metabolism in both cohorts. O2 consumption (h), CO2 production (i), RER (j), ambulatory activity (k), heat production (l) and food intake (m) were detected to examine energy expenditure. Data are shown as means±s.d. No difference was detected in this figure. CTR, control group; MOH, obesity history group; RER, respiratory exchange ratio.

Figure 3

Immunodeficiency leads to failure in establishing obesity memory. Immunodeficient Rag1−/− mice and C57BL/6J mice that were treated with dexamethasone (dexa) were subjected to a weight gain-loss-regain cycle. Body weight curve (a, c) and body weight increment ratio values during the weight regain period (b, d) were recorded to examine obesity memory in Rag1−/− mice (a, b) and dexa-treated C57BL/6J mice (c, d), respectively. Adoptive transfer of splenocytes was performed to determine the role of immune cells in memorizing obesity. The body weight curves of donor C57BL/6J mice (e, h) and recipient Rag1−/− mice (f, i) and the body weight increment ratios of recipients during HFD feeding (g, j) were recorded after weight loss (e–g) and after 1 month of weight maintenance (h–j), respectively. The cell collection time is indicated by a black arrow. Data are shown as means±s.d. ***P<0.001, unpaired Student’s t-test. §§§P<0.001, two-way ANOVA followed by the Bonferroni post hoc test. HFD, high fat diet; Ns, no significance.

Figure 4

Role of CD4+ T cells in establishing and storing obesity memory. CD4+T cell-deficient H2A−/− mice were subjected to the weight gain-loss-regain cycle. Body weight curve (a) and body weight increment ratio values during the weight regain period (b) were recorded to examine obesity memory in H2A−/− mice. MOH C57BL/6J mice were injected with an anti-CD4 antibody (dMOH) or corresponding isotype IgG (sMOH) to determine the role of CD4+ T cells in obesity memory. CTR C57BL/6J mice were injected with saline. The injection time is indicated with a black arrow. Body weight curve (c) and body weight increment ratio values during the weight regain period (d) were recorded to examine obesity memory. Adoptive transfer of CD4+ T cells was conducted to confirm their role in memorizing obesity. The body weight curves of donor C57BL/6J (e, h) and recipient Rag1−/− mice (f, i) and the body weight increment ratios of recipients during the HFD feeding period (g, j) were recorded after weight loss (e–g) and after 1 month of weight maintenance (h–j), respectively. The cell collection time is indicated by a black arrow. Data are shown as means±s.d. *P<0.05, **P<0.01 and ***P<0.001, unpaired Student’s t-test. §§§P<0.001, two-way ANOVA followed by the Bonferroni post hoc test. CTR, control group; dMOH, CD4+ T cell-deficient MOH group; HFD, high fat diet; mCD4T, CD4+ T cells carrying obesity memory group; MOH, obesity history group; NC, negative control group; Ns, no significance; PC, positive control group; sMOH, CD4+ T cell-sufficient MOH group.