Macrophage JAK2 deficiency protects against high-fat diet-induced inflammation

Desai, Harsh R.; Sivasubramaniyam, Tharini; Revelo, Xavier S.; Schroer, Stephanie A.; Luk, Cynthia T.; Rikkala, Prashanth Reddy; Metherel, Adam H.; Dodington, David W.; Park, Yoo Jin; Kim, Min Jeong; Rapps, Joshua A.; Besla, Rickvinder; Robbins, Clinton S.; Wagner, Kay Uwe; Bazinet, Richard P.; Winer, Daniel A.; Woo, Minna

doi:10.1038/s41598-017-07923-0

Cited by 40 publications

(28 citation statements)

References 57 publications

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“…We cannot exclude the possibility that dyslipidemia or hyperleptinemia may also contribute to the changes in monocyte maturity and phenotype that we observed with HF diet (Desai et al. ; Rahman et al. ; Short et al.…”

Section: Discussionmentioning

confidence: 89%

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TNF, but not hyperinsulinemia or hyperglycemia, is a key driver of obesity‐induced monocytosis revealing that inflammatory monocytes correlate with insulin in obese male mice

et al. 2018

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Inflammation contributes to obesity‐related hyperinsulinemia and insulin resistance, which often precede type 2 diabetes. Inflammation is one way that obesity can promote insulin resistance. It is not clear if the extent of obesity, hyperinsulinemia, or hyperglycemia, underpins changes in cellular immunity during diet‐induced obesity. In particular, the requirement for obesity or directionality in the relationship between insulin resistance and monocyte characteristics is poorly defined. Inflammatory cytokines such as tumor necrosis factor (TNF) can contribute to insulin resistance. It is unclear if TNF alters monocytosis or specific markers of cellular immunity in the context of obesity. We measured bone marrow and blood monocyte characteristics in WT and TNF −/− mice that were fed obesogenic, high fat (HF) diets. We also used hyperglycemic Akita mice and mice implanted with insulin pellets in order to determine if glucose or insulin were sufficient to alter monocyte characteristics. We found that diet‐induced obesity in male mice increased the total number of monocytes in blood, but not in bone marrow. Immature, inflammatory (Ly6Chigh) monocytes decreased within the bone marrow and increased within peripheral blood of HF‐fed mice. We found that neither hyperinsulinemia nor hyperglycemia was sufficient to induce the observed changes in circulating monocytes in the absence of diet‐induced obesity. In obese HF‐fed mice, antibiotic treatment lowered insulin and insulin resistance, but did not alter circulating monocyte characteristics. Fewer Ly6Chigh monocytes were present within the blood of HF‐fed TNF −/− mice in comparison to HF‐fed wild‐type (WT) mice. The prevalence of immature Ly6Chigh monocytes in the blood correlated with serum insulin and insulin resistance irrespective of the magnitude of adipocyte or adipose tissue hypertrophy in obese mice. These data suggest that diet‐induced obesity instigates a TNF‐dependent increase in circulating inflammatory monocytes, which predicts increased blood insulin and insulin resistance independently from markers of adiposity or adipose tissue expansion.

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Section: Discussionmentioning

confidence: 89%

“…; Desai et al. ). Adipose tissue macrophages in particular are derived from local proliferation, resident hematopoietic stem cells, and infiltration of peripheral blood monocytes (macrophage precursors) (Weisberg et al.…”

Section: Introductionmentioning

confidence: 99%

TNF, but not hyperinsulinemia or hyperglycemia, is a key driver of obesity‐induced monocytosis revealing that inflammatory monocytes correlate with insulin in obese male mice

et al. 2018

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“…Besides its clear role in the control of energy homeostasis and adipose tissue function, leptin is also very important in immune processes. For instance, it has been shown to participate in the activation and recruitment of immune cells, such as macrophages (15,60), neutrophils (18), and eosinophils (13). In obesity, adipose cells secrete large amounts of immunometabolic mediators that usually cause a derange in homeostasis (2,5,61,62).…”

Section: Discussionmentioning

confidence: 99%

“…Adipose tissue, which includes adipocytes and stromal cells, becomes chronically inflamed with enhanced secretion of proinflammatory mediators, such as TNF-α and IL-6, and a decrease in anti-inflammatory ones, such as IL-10 (5,63). Leptin was found to participate in the induction of proinflammatory cytokines in dendritic cells (17), T cells (17), and macrophages (15,44,60). In this report we show that leptin is a proinflammatory factor also in adipocytes, as shown by the increase in TNF-α and the decrease in IL-10 production by 3T3-L1 cells, and increased TNF-α and IL-6 in differentiated ASCs.…”

Section: Discussionmentioning

confidence: 99%

Leptin Induces Proadipogenic and Proinflammatory Signaling in Adipocytes

et al. 2019

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Background: Leptin is an adipokine with well-known effects on the central nervous system including the induction of energy expenditure and satiety. Leptin also has major relevance when activating immune cells and modulating inflammatory response. In obesity, increases in white adipose tissue accumulation and leptin levels are accompanied by hypothalamic resistance to leptin. Even though the adipose tissue is a leptin-rich environment, the local actions of leptin regarding adipogenesis were not thoroughly investigated until now. Here we evaluate the contributions of leptins direct signaling in preadipocytes and adipose tissue-derived stromal cells (ASCs) for adipogenesis.Methods: Adipocytes were differentiated from the murine lineage of preadipocytes 3T3-L1 or ASCs from subcutaneous and visceral (retroperitoneal) fat depots from C57Bl/6J mice. Differentiating cells were treated with leptin in addition to or in replacement of insulin. The advance of adipogenesis was assessed by the expression and secretion of adipogenesis-and lipogenesis-related proteins by Western blot and immunoenzimatic assays, and the accumulation of lipid droplets by fluorescence microscopy.Results: Leptin treatment in 3T3-L1 preadipocytes or ASCs increased the production of the adipogenesis-and lipogenesis-related proteins PLIN1, CAV-1, PPARγ, SREBP1C, and/or adiponectin at earlier stages of differentiation. In 3T3-L1 preadipocytes, we found that leptin induced lipid droplets' formation in an mTOR-dependent manner. Also, leptin induced a proinflammatory cytokine profile in 3T3-L1 and ASCs, modulating the production of TNF-α, IL-10, and IL-6. Since insulin is considered an essential factor for preadipocyte differentiation, we asked whether leptin would support adipogenesis in the absence of insulin. Importantly, leptin induced the formation of lipid droplets and the expression of adipogenesis-related proteins independently of insulin during the differentiation of 3T3-L1 cells and ASCs. Conclusions:Our results demonstrate that leptin induces intracellular signaling in preadipocytes and adipocytes promoting adipogenesis and modulating the secretion Palhinha et al.Leptin Induces Adipogenesis of inflammatory mediators. Also, leptin restores adipogenesis in the absence of insulin. These findings contribute to the understanding of the local signaling of leptin in precursor and mature adipose cells. The proadipogenic role of leptin unraveled here may be of especial relevance during obesity, when its central signaling is defective.

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“…Metformin inhibits the differentiation of monocytes to macrophages and decreases their infiltration into atherosclerotic plaques through AMPK-mediated inhibition of STAT3 (156). Similarly, in insulin resistance and diet-induced obesity, protective effects of ABCA1/APOA1 activity are STAT3-dependent, as is the antiinflammatory adipose tissue phenotype of mice with a myeloiddeficiency of JAK2 (157,158). STAT6, on its own, or in concert with the vasodilatorstimulated phosphoprotein (VASP) has immunoregulatory properties in the context of metabolic inflammation.…”

Section: Signal Transducers and Activators Of Transcriptionmentioning

confidence: 99%

Mechanisms of Macrophage Polarization in Insulin Signaling and Sensitivity

et al. 2020

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Type-2 diabetes (T2D) is a disease of two etiologies: metabolic and inflammatory. At the cross-section of these etiologies lays the phenomenon of metabolic inflammation. Whilst metabolic inflammation is characterized as systemic, a common starting point is the tissue-resident macrophage, who's successful physiological or aberrant pathological adaptation to its microenvironment determines disease course and severity. This review will highlight the key mechanisms in macrophage polarization, inflammatory and non-inflammatory signaling that dictates the development and progression of insulin resistance and T2D. We first describe the known homeostatic functions of tissue macrophages in insulin secreting and major insulin sensitive tissues. Importantly we highlight the known mechanisms of aberrant macrophage activation in these tissues and the ways in which this leads to impairment of insulin sensitivity/secretion and the development of T2D. We next describe the cellular mechanisms that are known to dictate macrophage polarization. We review recent progress in macrophage bio-energetics, an emerging field of research that places cellular metabolism at the center of immune-effector function. Importantly, following the advent of the metabolically-activated macrophage, we cover the known transcriptional and epigenetic factors that canonically and non-canonically dictate macrophage differentiation and inflammatory polarization. In closing perspectives, we discuss emerging research themes and highlight novel non-inflammatory or non-immune roles that tissue macrophages have in maintaining microenvironmental and systemic homeostasis.

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Macrophage JAK2 deficiency protects against high-fat diet-induced inflammation

Cited by 40 publications

References 57 publications

TNF, but not hyperinsulinemia or hyperglycemia, is a key driver of obesity‐induced monocytosis revealing that inflammatory monocytes correlate with insulin in obese male mice

TNF, but not hyperinsulinemia or hyperglycemia, is a key driver of obesity‐induced monocytosis revealing that inflammatory monocytes correlate with insulin in obese male mice

Leptin Induces Proadipogenic and Proinflammatory Signaling in Adipocytes

Mechanisms of Macrophage Polarization in Insulin Signaling and Sensitivity

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