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Eosinophils and type 2 cytokine signaling in macrophages orchestrate

development of functional beige fat


SUMMARY

Beige fat, which expresses the thermogenic protein UCP1, provides a defense against cold
and obesity. Although a cold environment is the physiologic stimulus for inducing beige fat in
mice and humans, the events that lead from the sensing of cold to the development of beige
fat remain poorly understood. Here, we identify the efferent beige fat thermogenic circuit,
consisting of eosinophils, type 2 cytokines interleukin (IL)-4/13 and alternatively activated
macrophages. Genetic loss of eosinophils or IL-4/13 signaling impairs cold-induced
biogenesis of beige fat. Mechanistically, macrophages recruited to cold-stressed subcutaneous
white adipose tissue (scWAT) undergo alternative activation to induce tyrosine hydroxylase
expression and catecholamine production, factors required for browning of scWAT.
Conversely, administration of IL-4 to thermoneutral mice increases beige fat mass and
thermogenic capacity to ameliorate preestablished obesity. Together, our findings have
uncovered the efferent circuit controlling biogenesis of beige fat and provide support for its
targeting to treat obesity.

Systemically dispersed innate IL-13expressing cells in type 2 immunity


Type 2 immunity is a stereotyped host response to allergens and parasitic helminths that is
sustained in large part by the cytokines IL-4 and IL-13. Recent advances have called attention
to the contributions by innate cells in initiating adaptive immunity, including a novel lineagenegative population of cells that secretes IL-13 and IL-5 in response to the epithelial
cytokines IL-25 and IL-33. Here, we use IL-4 and IL-13 reporter mice to track lineagenegative innate cells that arise during type 2 immunity or in response to IL-25 and IL-33 in
vivo. Unexpectedly, lineage-negative IL-25 (and IL-33) responsive cells are widely
distributed in tissues of the mouse and are particularly prevalent in mesenteric lymph nodes,
spleen, and liver. These cells expand robustly in response to exogenous IL-25 or IL-33 and
after infection with the helminth Nippostrongylus brasiliensis, and they are the major innate
IL-13expressing cells under these conditions. Activation of these cells using IL-25 is
sufcient for worm clearance, even in the absence of adaptive immunity. Widely dispersed
innate type 2 helper cells, which we designate Ih2 cells, play an integral role in type 2
immune responses.

The immune cells in adipose tissue


Although the pathological role of the immune system in several metabolic disorders,
including type 1 diabetes mellitus (T1DM) and Addisons disease, has long been recognized

and studied, only in the last decade has it become apparent that the immune system plays a
broad and more subtle role in local and systemic metabolism. It is now apparent that the
immune system monitors and responds to specic metabolic cues in both pathologic and nonpathologic settings through a set of processes dubbed immunometabolism. Expansion of
adipose tissue mass, activation of lipolysis, eating a high fat diet and even non-shivering
thermogenesis all lead to the recruitment and activation of immune cells in key metabolic
tissues. The responses are complex and not completely dened, and indeed, as is typical of
rapidly evolving research areas, there are some conicting reports, especially related to the
metabolic consequences of manipulation of immune function. However, what is clear is the
consensus that metabolic processes, especially obesity and obesity-related complications,
activate both the innate and adaptive arms of the immune system. Canonical immune
processes consist of discrete steps: surveillance, recognition, effector action and resolution.
Over the last decade evidence for each part of the immune response has been found at the
intersection of the immune system with metabolism. Although evidence for immune
surveillance and modulation of metabolism has been found in the liver, muscle, hypothalamus
and pancreas, immune cell function has been most intensively studied and best understood in
adipose tissue where studies continue to provide insights into the intersection of the metabolic
and immune systems. Here we review the modulation of immune cell populations in adipose
tissue and discuss regulatory processes implicated in controlling the interface between
metabolism and immunologic function.

Type 1/Type 2 Immunity in Infectious Diseases


T helper type 1 (Th1) lymphocytes secrete secrete interleukin (IL)-2, interferon-g, and
lymphotoxin-a and stimulate type 1 immunity, which is characterized by intense phagocytic
activity. Conversely, Th2 cells secrete IL-4, IL-5, IL-9, IL-10, and IL-13 and stimulate type 2
immunity, which is characterized by high antibody titers. Type 1 and type 2 immunity are not
strictly synonymous with cell-mediated and humoral immunity, because Th1 cells also
stimulate moderate levels of antibody production, whereas Th2 cells actively suppress
phagocytosis. For most infections, save those caused by large eukaryotic pathogens, type 1
immunity is protective, whereas type 2 responses assist with the resolution of cell-mediated
inammation. Severe systemic stress, immunosuppression, or overwhelming microbial
inoculation causes the immune system to mount a type 2 response to an infection normally
controlled by type 1 immunity. In such cases, administration of antimicrobial chemotherapy
and exogenous cytokines restores systemic balance, which allows successful immune
responses to clear the infection

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