Similar to obesity, aging is associated with visceral adiposity and insulin resistance. Inflammation in adipose tissue, mainly evidenced by increased accumulation and proinflammatory polarization of T cells and macrophages, has been well-documented in obesity and may contribute to the associated metabolic dysfunctions including insulin resistance. Studies show that increased inflammation, including inflammation in adipose tissue, also occurs in aging, so-called “inflamm-aging.” Aging-associated inflammation in adipose tissue has some similarities but also differences compared to obesity-related inflammation. In particular, conventional T cells are elevated in adipose tissue in both obesity and aging and have been implicated in metabolic functions in obesity. However, the changes and also possibly functions of regulatory T cells (Treg) in adipose tissue are different in aging and obesity. In this review, we will summarize recent advances in research on the changes of these immune cells in adipose tissue with aging and obesity and discuss their possible contributions to metabolism and the potential of these immune cells as novel therapeutic targets for prevention and treatment of metabolic diseases associated with aging or obesity.

CD11c+ macrophages/dendritic cells (MDCs) are increased and display the classically activated M1-like phenotype in obese adipose tissue (AT) and may contribute to AT inflammation and insulin resistance. Stat1 is a key transcription factor for MDC polarization into the M1-like phenotype. Here, we examined the role of Stat1 in obesity-induced AT MDC polarization and inflammation and insulin resistance using mice with specific knockout of Stat1 in MDCs (cKO). Stat1 was upregulated and phosphorylated, indicating activation, early and persistently in AT and AT MDCs of wild-type mice fed a high-fat diet (HFD). Compared with littermate controls, cKO mice fed an HFD (16 weeks) had reductions in MDC (mainly CD11c+ macrophage) M1-like polarization and interferon-γ–expressing T-helper type 1 (Th1) cells but increases in interleukin 5–expressing Th2 cells and eosinophils in perigonadal and inguinal AT, and enhanced inguinal AT browning, with increased energy expenditure. cKO mice compared with controls also had significant reductions in triglyceride content in the liver and skeletal muscle and exhibited improved insulin sensitivity and glucose tolerance. Taken together, our results demonstrate that Stat1 in MDCs plays an important role in obesity-induced MDC M1-like polarization and AT inflammation and contributes to insulin resistance and metabolic dysfunctions in obese mice.

<a>CD11c⁺ macrophages/dendritic cells (MDCs) are increased and display classically activated M1-like phenotype in obese adipose tissue (AT) and may contribute to AT inflammation and insulin resistance. Stat1 is a key transcription factor for MDC polarization into M1-like phenotype. Here, we examined the role of Stat1 in obesity-induced AT MDC polarization and inflammation and insulin resistance using mice with specific knockout of Stat1 in MDCs (cKO). Stat1 was upregulated and phosphorylated, indicating activation, early and persistently in AT and AT MDCs of wild-type mice fed high-fat diet (HFD). Compared to littermate controls, cKO mice fed HFD (16 weeks) had reductions in MDC (mainly CD11c⁺ macrophage) M1-like polarization and interferon-</a>g–expressing T helper type 1 (Th1) cells, but increases in interleukin-5–expressing Th2 cells and eosinophils in perigonadal and inguinal AT, and enhanced inguinal AT browning, with increased energy expenditure. cKO mice compared with controls also had significant reductions in triglyceride content in the liver and skeletal muscle and exhibited improved insulin sensitivity and glucose tolerance. Taken together, our results demonstrated that Stat1 in MDCs plays an important role in obesity-induced MDC M1-like polarization and AT inflammation and contributes to insulin resistance and metabolic dysfunctions in obese mice.

Introduction: Clinical trials suggest that low-saturated fat diet (LSFD) may reduce the risk of atherosclerotic cardiovascular disease (ASCVD) in subjects with hypertriglyceridemia (HTG). Monocytes play crucial roles in atherogenesis. Hypothesis: LSFD vs high-saturated fat diet (HSFD) improves monocyte phenotypes, thereby reducing ASCVD risk, in subjects with HTG. Methods: Subjects with HTG and metabolic syndrome (MetS, n=19) received isocaloric LSFD (~25% of calories from fat, 5% from saturated fat) and HSFD (~52% of calories from fat, 25% from saturated fat) in randomized order for 4 days (days 1-4) plus a breakfast on day 5, separated by a 4- to 6-week washout period. Blood was drawn on day 1 fasting before the diets and 3 times on day 5 (fasting before the breakfast and 4 and 6 hours postprandial) for measurement of lipid profile and analyses of monocyte phenotypes by flow cytometry and monocyte adhesion by a lab-on-a-chip microfluidic assay. Results: On day 5, LSFD, compared to HSFD, induced lower plasma levels of postprandial total triglyceride and LDL-triglyceride and fasting and postprandial total cholesterol, LDL-cholesterol, and small dense LDL-cholesterol. Compared to HSFD, LSFD reduced fasting and postprandial intracellular lipid accumulation in classical and intermediate monocytes examined by nile red staining and indicated by side scatter value of flow cytometric analysis. LSFD versus HSFD also reduced ex vivo uptake of oxidized LDL by classical monocytes at 4 hours postprandially and by intermediate monocytes in fasting state. Surface levels of molecules involved in monocyte adhesion/migration, including CD11c, CD81, and CCR2, were lower on monocytes with LSFD than with HSFD. Consistently, LSFD compared to HSFD reduced monocyte adhesion to VCAM-1. Intracellular levels of cytokines such as IL-1β, TNFα, and IL-6 in monocytes showed no difference between the two diets. Conclusions: In subjects with HTG and MetS, short-term LSFD compared to HSFD reduces monocyte intracellular lipid accumulation and improves monocyte phenotypes with reductions in monocyte adhesion and oxidized LDL uptake. These findings highlight the importance of diet composition in monocyte phenotypes and possibly atherosclerosis risks in patients with HTG and MetS.

Background: Obesity is a global epidemic and major risk factor for insulin resistance and type 2 diabetes. Obesity is associated with low grade chronic inflammation of adipose tissue (AT). F4/80+CD11c+ macrophages/dendritic cells are increased and polarized into M1-like phenotypes in AT and may contribute to insulin resistance in mouse models of obesity. STAT1 is a transcription factor that play key roles in macrophage polarization into M1-like phenotypes. Hence, we investigated the role of CD11c+ macrophage/dendritic cell STAT1 in obesity-induced AT inflammation and insulin resistance. Methods: Mice with specific knockout of STAT1 in CD11c+ cells were generated by crossbreeding STAT1 fl/fl and CD11c-Cre mice. CD11c/STAT1 KO and littermate controls were fed either high fat diet (HFD, for 16 weeks) to induce obesity or normal diet (ND) as lean controls. We evaluated body composition, insulin sensitivity, gene expression of inflammatory markers, various immune cells and brown/beige adipogenesis markers in AT. Results: Perigonadal white AT (PWAT) and body weight were not significantly different between KO and control groups but liver weight and liver-to-body weight ratio were significantly reduced in obese KO mice (p&lt;0.05). STAT1 KO mice on HFD exhibited improved insulin sensitivity examined by insulin tolerance test (p&lt;0.05) and reduced expression of inflammatory markers TNFα, IFNγ, IL-12 and MCP1 in PWAT and subcutaneous AT (SAT) compared to littermate controls (p&lt;0.05). AT immune cell analysis revealed that STAT1 ablation caused a decrease in M1-like proinflammatory polarization and increase in M2-like polarization of F4/80+ macrophages, reduced number of total CD3+ T cells and CD8+T cells in PWAT. In addition, brown/beige adipogenesis markers UCP1, CIDEA and Prdm16 also upregulated (p&lt;0.05) in SAT of obese KO mice. Conclusion: Our results show the critical role of macrophage/dendritic cell STAT1 in obesity-induced AT inflammation and insulin resistance. Disclosure A. Kalathookunnel Antony: None. X.D. Perrard: None. Z. Lian: None. J. Perrard: None. L. Hennighausen: None. C.W. Smith: None. C.M. Ballantyne: Research Support; Self; Abbott, Amarin Corporation, Amgen Inc., Esperion Therapeutics, Ionis Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., Regeneron Pharmaceuticals, Inc., Roche Diagnostics Corporation, Sanofi. Consultant; Self; Abbott, Amarin Corporation, Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Esperion Therapeutics, Ionis Pharmaceuticals, Inc., Matinas BioPharma, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Pfizer Inc., Regeneron Pharmaceuticals, Inc., Roche Diagnostics Corporation, Sanofi. H. Wu: None.