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Macrophages Mediate Increased CD8 T Cell Inflammation During Weight Loss in Formerly Obese Mice.

ABSTRACT: Even after successful weight reduction, obese adults tend to quickly regain the lost weight. This raises the question of whether weight loss improves the underlying chronic adipose tissue inflammation characteristic of obesity. In order to improve our understanding of the mechanisms that reshape metabolic organs during weight loss, we investigated the macrophage and T cell function of the liver and adipose tissue on reversing high fat diet (HFD) mice to normal control diet (NCD). Obese mice that were switched to NCD showed an improvement in their metabolic profile that included enhanced glucose and insulin tolerance, decreased cholesterol, triglyceride, serum glutamic-oxaloacetic transaminase (SGOT), and serum glutamic pyruvic transaminase (SGPT) levels that were comparable to NCD controls. However, despite weight loss, increased frequencies, but not total numbers, of IL-17+ and IL-22+ CD4+ T cells, IFN-?+ and TNF+ CD8+ T cells and IL-17+ and IL-22+ CD8+ T cells were observed in the adipose tissue of mice switched from HFD to NCD compared to NCD and even HFD fed mice. Further, in the liver, IFN-?+ and TNF+ CD8+ T cell, IL-17+ and IL-22+ CD8+ T cell, macrophage frequencies and their expression of antigen presenting molecules were increased. To determine if macrophages are the major determinants of the sustained inflammation observed during weight loss, we depleted macrophages, which significantly reduced IFN-?+, TNF+, IL-17+, and IL-22+ CD8+ T cell frequencies in the liver and the adipose tissue. In conclusion, we show that although weight loss improves the metabolic profile, there is an active and ongoing CD8+ T cell inflammation in liver and adipose tissue mediated by macrophages.

SUBMITTER: Surendar J

PROVIDER: S-EPMC7198814 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Macrophages Mediate Increased CD8 T Cell Inflammation During Weight Loss in Formerly Obese Mice.

Surendar Jayagopi J Karunakaran Indulekha I Frohberger Stefan J SJ Koschel Marianne M Hoerauf Achim A Hübner Marc P MP

Frontiers in endocrinology 20200428

Even after successful weight reduction, obese adults tend to quickly regain the lost weight. This raises the question of whether weight loss improves the underlying chronic adipose tissue inflammation characteristic of obesity. In order to improve our understanding of the mechanisms that reshape metabolic organs during weight loss, we investigated the macrophage and T cell function of the liver and adipose tissue on reversing high fat diet (HFD) mice to normal control diet (NCD). Obese mice that ...[more]

PMID: 32411095

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Project description:BackgroundIntermittent severe energy restriction is popular for weight management. To investigate whether intermittent moderate energy restriction may improve this approach by enhancing weight loss efficiency, we conducted a study in mice, where energy intake can be controlled.MethodsMale C57/Bl6 mice that had been rendered obese by an ad libitum diet high in fat and sugar for 22 weeks were then fed one of two energy-restricted normal chow diets for a 12-week weight loss phase. The continuous diet (CD) provided 82% of the energy intake of age-matched ad libitum chow-fed controls. The intermittent diet (ID) provided cycles of 82% of control intake for 5-6 consecutive days, and ad libitum intake for 1-3 days. Weight loss efficiency during this phase was calculated as (total weight change) ÷ [(total energy intake of mice on CD or ID)-(total average energy intake of controls)]. Subsets of mice then underwent a 3-week weight regain phase involving ad libitum re-feeding.ResultsMice on the ID showed transient hyperphagia relative to controls during each 1-3-day ad libitum feeding period, and overall ate significantly more than CD mice (91.1±1.0 versus 82.2±0.5% of control intake respectively, n = 10, P<0.05). There were no significant differences between CD and ID groups at the end of the weight loss or weight regain phases with respect to body weight, fat mass, circulating glucose or insulin concentrations, or the insulin resistance index. Weight loss efficiency was significantly greater with ID than with CD (0.042±0.007 versus 0.018±0.001 g/kJ, n = 10, P<0.01). Mice on the CD exhibited significantly greater hypothalamic mRNA expression of proopiomelanocortin (POMC) relative to ID and control mice, with no differences in neuropeptide Y or agouti-related peptide mRNA expression between energy-restricted groups.ConclusionIntermittent moderate energy restriction may offer an advantage over continuous moderate energy restriction, because it induces significantly greater weight loss relative to energy deficit in mice.

Project description:BackgroundObesity is a risk factor for breast cancer, and women with obesity that develop breast cancer have a worsened prognosis. Within the mammary gland, obesity causes chronic, macrophage-driven inflammation and adipose tissue fibrosis. Weight loss is a recommended intervention to resolve obesity, but the impact of weight loss on the mammary gland microenvironment and in tumors has not been well identified.MethodsTo examine the effects of weight loss following obesity, mice were fed a high-fat diet for 16 weeks to induce obesity, then switched to a low-fat diet for 6 weeks. We examined changes in immune cells, including fibrocytes, which are myeloid lineage cells that have attributes of both macrophages and myofibroblasts, and collagen deposition within the mammary glands of non-tumor-bearing mice and within the tumors of mice that were transplanted with estrogen receptor alpha positive TC2 tumor cells.ResultsIn formerly obese mice, we observed reduced numbers of crown-like structures and fibrocytes in mammary glands, while collagen deposition was not resolved with weight loss. Following transplant of TC2 tumor cells into the mammary glands of lean, obese, and formerly obese mice, diminished collagen deposition and cancer-associated fibroblasts were observed in tumors from formerly obese mice compared to obese mice. Within tumors of obese mice, increased myeloid-derived suppressor cells and diminished CD8+ T cells were identified, while the microenvironment of tumors of formerly obese mice were more similar to tumors from lean mice. When TC2 tumor cells were mixed with CD11b+CD34+ myeloid progenitor cells, which are the cells of origin for fibrocytes, and transplanted into mammary glands of lean and obese mice, collagen deposition within the tumors of both lean and obese was significantly greater than when tumor cells were mixed with CD11b+CD34- monocytes or total CD45+ immune cells.ConclusionsOverall, these studies demonstrate that weight loss resolved some of the microenvironmental conditions within the mammary gland that may contribute to tumor progression. Additionally, fibrocytes may contribute to early collagen deposition in mammary tumors of obese mice leading to the growth of desmoplastic tumors.

Dataset Information

Macrophages Mediate Increased CD8 T Cell Inflammation During Weight Loss in Formerly Obese Mice.

Publications

Macrophages Mediate Increased CD8 T Cell Inflammation During Weight Loss in Formerly Obese Mice.

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