MFehi adipose tissue macrophages compensate for tissue iron perturbations in mice.

Resident adipose tissue macrophages (ATMs) play multiple roles to maintain tissue homeostasis, such as removing excess free fatty acids and regulation of the extracellular matrix. The phagocytic nature and oxidative resiliency of macrophages not only allows them to function as innate immune cells but also to respond to specific tissue needs, such as iron homeostasis. MFehi ATMs are a subtype of resident ATMs that we recently identified to have twice the intracellular iron content as other ATMs and elevated expression of iron-handling genes. Although studies have demonstrated that iron homeostasis is important for adipocyte health, little is known about how MFehi ATMs may respond to and influence adipose tissue iron availability. Two methodologies were used to address this question: dietary iron supplementation and intraperitoneal iron injection. Upon exposure to high dietary iron, MFehi ATMs accumulated excess iron, whereas the iron content of MFelo ATMs and adipocytes remained unchanged. In this model of chronic iron excess, MFehi ATMs exhibited increased expression of genes involved in iron storage. In the injection model, MFehi ATMs incorporated high levels of iron, and adipocytes were spared iron overload. This acute model of iron overload was associated with increased numbers of MFehi ATMs; 17% could be attributed to monocyte recruitment and 83% to MFelo ATM incorporation into the MFehi pool. The MFehi ATM population maintained its low inflammatory profile and iron-cycling expression profile. These studies expand the field's understanding of ATMs and confirm that they can respond as a tissue iron sink in models of iron overload.

Elevating adipose eosinophils in obese mice to physiologically normal levels does not rescue metabolic impairments.

OBJECTIVE: Obesity is a metabolic disorder that has reached epidemic proportions worldwide and leads to increased risk for diabetes, cardiovascular disease, asthma, certain cancers, and various other diseases. Obesity and its comorbidities are associated with impaired adipose tissue (AT) function. In the last decade, eosinophils have been identified as regulators of proper AT function. Our study aimed to determine whether normalizing the number of AT eosinophils in obese mice, to those of lean healthy mice, would reduce obesity and/or improve metabolic fitness. METHODS: C57BL/6J mice fed a high fat diet (HFD) were simultaneously given recombinant interleukin-5 (rIL5) for 8 weeks to increase AT eosinophils. Metabolic fitness was tested by evaluating weight gain, AT inflammation, glucose, lipid, and mixed-meal tolerance, AT insulin signaling, energy substrate utilization, energy expenditure, and white AT beiging capacity. RESULTS: Eosinophils were increased ∼3-fold in AT of obese HFD-fed mice treated with rIL5, and thus were restored to levels observed in lean healthy mice. However, there were no significant differences in rIL5-treated mice among the above listed comprehensive set of metabolic assays, despite the increased AT eosinophils. CONCLUSIONS: We have shown that restoring obese AT eosinophils to lean healthy levels is not sufficient to allow for improvement in any of a range of metabolic features otherwise impaired in obesity. Thus, the mechanisms that identified eosinophils as positive regulators of AT function, and therefore systemic health, are more complex than initially understood and will require further study to fully elucidate.

CC-chemokine receptor 7 (CCR7) deficiency alters adipose tissue leukocyte populations in mice.

The mechanism by which macrophages and other immune cells accumulate in adipose tissue (AT) has been an area of intense investigation over the past decade. Several different chemokines and their cognate receptors have been studied for their role as chemoattractants in promoting recruitment of immune cells to AT However, it is also possible that chemoattractants known to promote clearance of immune cells from tissues to regional lymph nodes might be a critical component to overall AT immune homeostasis. In this study, we evaluated whether CCR7 influences AT macrophage (ATM) or T-cell (ATT) accumulation. CCR7-/- and littermate wild-type (WT) mice were placed on low-fat diet (LFD) or high-fat diet (HFD) for 16 weeks. CCR7 deficiency did not impact HFD-induced weight gain, hepatic steatosis, or glucose intolerance. Although lean CCR7-/- mice had an increased proportion of alternatively activated ATMs, there were no differences in ATM accumulation or polarization between HFD-fed CCR7-/- mice and their WT counterparts. However, CCR7 deficiency did lead to the preferential accumulation of CD8+ ATT cells, which was further exacerbated by HFD feeding. Finally, expression of inflammatory cytokines/chemokines, such as Tnf, Il6, Il1ß, Ccl2, and Ccl3, was equally elevated in AT by HFD feeding in CCR7-/- and WT mice, while Ifng and Il18 were elevated by HFD feeding in CCR7-/- but not in WT mice. Together, these data suggest that CCR7 plays a role in CD8+ATT cell egress, but does not influence ATM accumulation or the metabolic impact of diet-induced obesity.

Role of lipids in the metabolism and activation of immune cells.

Immune cell plasticity has extensive implications in the pathogenesis and resolution of metabolic disorders, cancers, autoimmune diseases and chronic inflammatory disorders. Over the past decade, nutritional status has been discovered to influence the immune response. In metabolic disorders such as obesity, immune cells interact with various classes of lipids, which are capable of controlling the plasticity of macrophages and T lymphocytes. The purpose of this review is to discuss lipids and their impact on innate and adaptive immune responses, focusing on two areas: (1) the impact of altering lipid metabolism on immune cell activation, differentiation and function and (2) the mechanism by which lipids such as cholesterol and fatty acids regulate immune cell plasticity.

Iron homeostasis: a new job for macrophages in adipose tissue?

Elevated serum ferritin and increased cellular iron concentrations are risk factors for diabetes; however, the etiology of this association is unclear. Metabolic tissues such as pancreas, liver, and adipose tissue (AT), as well as the immune cells resident in these tissues, may be involved. Recent studies demonstrate that the polarization status of macrophages has important relevance to their iron-handling capabilities. Furthermore, a subset of macrophages in AT have elevated iron concentrations and a gene expression profile indicative of iron handling, a capacity diminished in obesity. Because iron overload in adipocytes increases systemic insulin resistance, iron handling by AT macrophages may have relevance not only to adipocyte iron stores but also to local and systemic insulin sensitivity.

Mathematical estimates of recovery after loss of activity: II. Long-range connectivity facilitates rapid functional recovery.

OBJECTIVE: To model the effects of system connectedness on recovery of dysfunctional tissues. DESIGN: One-dimensional elementary cellular automata models with small-world features, where the center-input for a few cells comes not from itself but, with a given probability, from another cell. This probability represents the connectivity of the network. The long-range connections are chosen randomly to survey the potential influences of distant information flowing into a local region. SETTING: MATLAB and Mathematica computing environments. PATIENTS: None. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We determined the recovery rate of the entropy after perturbing a uniformly dormant system. We observed that the recovery of normal activity after perturbation of a dormant system had the characteristics of an epidemic. Moreover, we found that the rate of recovery to normal steady-state activity increased rapidly even for small amounts of long-range connectivity. Findings obtained through numerical simulation were verified through analytical solutions. CONCLUSIONS: This study links our hypothesis that multiple organ function syndromes represent recoupling failure with a mathematical model showing the contribution of such coupling to reactivation of dormant systems. The implication is that strategies aimed not at target tissues or target organs but rather at restoring the quality and quantity of interconnections across those tissues and organs may be a novel therapeutic strategy.