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Anti-Inflammatory State in the Fat Tissue: Role of the Sympathetic Nerves by an Inhibition of Macrophage TNF-α Expression

sympathetic nerves anti-inflammatory state
Anti-inflammatory state in fat tissue-sympathetic nerves

New report, published in Endocrinology, indicates that the sympathetic nerves keep up an anti-anflammatory state in the fat tissue.

More specifically, the activity of the sympathetic nervous system (SNS) and its β2-adrenoceptor signaling pathway sustain low levels of the production of the pro-inflammatory cytokine tumor necrosis factor (TNF)-α in macrophages of lean mice.

Adipose tissue macrophages (ATMs) are a specialized type of leukocyte present in lean and obese states that contribute to adipose tissue inflammation and remodeling in mammals. ATMs in mice are classified into 2 general subtypes based on functional characteristics.

Resident ATMs that manifest properties that overlap with those of alternatively activated (M2) macrophages and are associated with suppression of the immune response, and CD11c-positive cells that are associated with tissue damage, proinflammatory signaling, and the generation of T helper 1 cytokines such as TNF-α, a hallmark of classically activated (M1) macrophages.

Pro-inflammatory macrophages play a key role in the pathogenesis of the systemic low-grade chronic inflammation, associated with obesity and insulin resistance (Angela Castoldi et al., Front Immunol, 2016, 6:637).

ATMs in adipose tissue of lean animals are anti-inflammatory (2, 3), and the pathological factors that induce a functional transition in ATM polarization from M2 to M1 are therefore of interest. Saturated fatty acids activate inflammatory programs in resident ATMs. Toll-like pattern recognition receptors, in particular Toll-like receptor (TLR)4, mediate the proinflammatory effects of saturated fatty acids as well as those of lipopolysaccharide (LPS).

The abundance of inflammatory cytokines such as TNF-α is increased in brown adipose tissue (BAT) as well as in white adipose tissue (WAT) of obese animals (6). TNF-α suppresses the expression of uncoupling protein-1 (UCP-1) in brown adipocytes.

How resident macrophages’ function is regulated, in lean animals, remains poorly understood. It is known, however that the adipose tissue is heavily innervated by sympathetic/noradrenergic nerves.

The sympathetic nervous system (SNS) regulates lipid metabolism in adipose tissue. The central melanocortin system, in which α-melanocyte-stimulating hormone and agouti-related neuropeptide (AgRP) reciprocally control the activity of the melanocortin receptor (MCR), regulates lipid metabolism in WAT. Stimulation of central MCRs with the synthetic agonist melanotan II (MT-II) thus increases lipolysis in WAT via the SNS, whereas inhibition of MCRs increases expression of lipogenic genes in WAT.

Electrical stimulation of the medial hypothalamus stimulates thermogenesis as well as regulates glucose and lipid metabolism in BAT via sympathetic nerves innervating the tissue. The β3-adrenergic receptor (AR) is implicated in norepinephrine (NE)-induced lipolysis in WAT and thermogenesis in BAT. Catecholamines produced by ATMs have also been implicated in adaptive thermogenesis in WAT.

The study in Endocrinology by Lijun Tang and colleagues from the National Institute for Physiological Sciences, Okazaki, Aichi, Japan indicates that sympathetic nerves, innervating adipose tissue, down-regulate local TNF-α secretion directly via an effect on β2-adrenoceptors expressed by macrophages. The study also demonstrates that the brain melanocortin pathway is involved in the regulation of the anti-inflammatory state in lean mice via SNS-related mechanisms.

The authors suggest that, in the fat tissue of lean animals, a longstanding suppression of the β-adrenoceptor function may keep the balance of anti-inflammatory versus inflammatory state towards anti-inflammation, and this effect is not related to impairment of thermogenic function.

In conclusion, Lijun Tang and colleagues found that the SNS and β2-AR-PKA pathway suppress TNF-α production in adipose tissue of lean mice. The sympathetic nerve-immune system interface and the anti-inflammatory SNS impact on macrophages might be dysfunctional in obese animals, and perhaps, in humans with obesity.

Source: Endocrinology, 2015, 156:3680-94.
Read More: Endocrinology


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