Article

Eosinophils Sustain Adipose Alternatively Activated Macrophages Associated with Glucose Homeostasis

Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143-0795, USA.
Science (Impact Factor: 33.61). 03/2011; 332(6026):243-7. DOI: 10.1126/science.1201475
Source: PubMed

ABSTRACT

Eosinophils are associated with helminth immunity and allergy, often in conjunction with alternatively activated macrophages (AAMs). Adipose tissue AAMs are necessary to maintain glucose homeostasis and are induced by the cytokine interleukin-4 (IL-4). Here, we show that eosinophils are the major IL-4-expressing cells in white adipose tissues of mice, and, in their absence, AAMs are greatly attenuated. Eosinophils migrate into adipose tissue by an integrin-dependent process and reconstitute AAMs through an IL-4- or IL-13-dependent process. Mice fed a high-fat diet develop increased body fat, impaired glucose tolerance, and insulin resistance in the absence of eosinophils, and helminth-induced adipose tissue eosinophilia enhances glucose tolerance. Our results suggest that eosinophils play an unexpected role in metabolic homeostasis through maintenance of adipose AAMs.

    • "Regulatory T cell numbers decrease in favor of IFN producing Th1 and NKT cells[76,82,123]. ILC2 and eosinophil numbers decline with the increase in adipose tissue mass, which facilitates M1 ATM polarization[83,84]. B cells form a local source of IgG antibodies that promote insulin resistance through an unknown mechanism[124]. "
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    ABSTRACT: Adipose tissue provides the body with a storage depot of nutrients that is drained during times of starvation and replenished when food sources are abundant. As such, it is the primary sensor for nutrient availability in the milieu of an organism, which it communicates to the body through the excretion of hormones. Adipose tissue regulates a multitude of body functions associated with metabolism, such as gluconeogenesis, feeding and nutrient uptake. The immune system forms a vital layer of protection against micro-organisms that try to gain access to the nutrients contained in the body. Because infections need to be resolved as quickly as possible, speed is favored over energy-efficiency in an immune response. Especially when immune cells are activated, they switch to fast, but energy-inefficient anaerobic respiration to fulfill their energetic needs. Despite the necessity for an effective immune system, it is not given free rein in its energy expenditure. Signals derived from adipose tissue limit immune cell numbers and activity under conditions of nutrient shortage, whereas they allow proper immune cell activity when food sources are sufficiently available. When excessive fat accumulation occurs, such as in diet-induced obesity, adipose tissue becomes the site of pathological immune cell activation, causing chronic low-grade systemic inflammation. Obesity is therefore associated with a number of disorders in which the immune system plays a central role, such as atherosclerosis and non-alcoholic steatohepatitis. In this review, we will discuss the way in which adipose tissue regulates activity of the immune system under healthy and pathological conditions.
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    • "Obesity and diabetes involve chronic inflammation (Gregor and Hotamisligil, 2011) mediated by a repertoire of inflammatory cells, including macrophages, B cells, T cells, neutrophils, eosinophils , and mast cells (MCs) (Weisberg et al., 2003; DeFuria et al., 2013; Matarese et al., 2012; Talukdar et al., 2012; Wu et al., 2011; Liu et al., 2009). We previously established that activated MCs operate in diet-induced obesity (DIO) and diabetes in mice by releasing interferon-g (IFN-g) and interleukin-6 (IL6), cysteinyl cathepsins, chymase, and tryptase to activate vascular cells or adipocytes and promote adipose tissue angiogenesis, liver glycogenesis, and adipocyte differentiation (Liu et al., 2009). "
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    ABSTRACT: Mast cells (MCs) contribute to the pathogenesis of obesity and diabetes. This study demonstrates that leptin deficiency slants MCs toward anti-inflammatory functions. MCs in the white adipose tissue (WAT) of lean humans and mice express negligible leptin. Adoptive transfer of leptin-deficient MCs expanded ex vivo mitigates diet-induced and pre-established obesity and diabetes in mice. Mechanistic studies show that leptin-deficient MCs polarize macrophages from M1 to M2 functions because of impaired cell signaling and an altered balance between pro- and anti-inflammatory cytokines, but do not affect T cell differentiation. Rampant body weight gain in ob/ob mice, a strain that lacks leptin, associates with reduced MC content in WAT. In ob/ob mice, genetic depletion of MCs exacerbates obesity and diabetes, and repopulation of ex vivo expanded ob/ob MCs ameliorates these diseases.
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    • "Innate immune pathways are known to control adipose tissue function and systemic glucose homeostasis (Molofsky et al., 2013; Wu et al., 2011). Interestingly, decreased group 2 innate lymphoid cells (ILC2) in WAT are associated with obesity in humans and mice (Brestoff and Artis, 2015). "
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    ABSTRACT: Since brown adipose tissue (BAT) dissipates energy through UCP1, BAT has garnered attention as a therapeutic intervention for obesity and metabolic diseases including type 2 diabetes. As we better understand the physiological roles of classical brown and beige adipocytes, it is becoming clear that BAT is not simply a heat-generating organ. Increased beige fat mass in response to a variety of external/internal cues is associated with significant improvements in glucose and lipid homeostasis that may not be entirely mediated by UCP1. We aim to discuss recent insights regarding the developmental lineages, molecular regulation, and new functions for brown and beige adipocytes.
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