Immune cell cholinergic signaling in adipose thermoregulation and immunometabolism

Shim

et al. 2022

Preprint

Obesity-mediated hypoxic stress underlies inflammatory responses, including interferon (IFN)-γ production by natural killer (NK) cells in white adipose tissue. However, the effects of obesity on NK cell IFN-γ production remain obscure. We demonstrate that hypoxia promotes xCT-mediated glutamate excretion and C-X-C motif chemokine ligand 12 (CXCL12) expression in hypertrophic adipocytes, leading to NK cell recruitment. Interestingly, the spatial proximity between NK cells and xCT-expressing adipocytes increases IFN-γ production by stimulating metabotropic glutamate receptor 5 (mGluR5) in NK cells, and IFN-γ further augments the expression of xCT and CXCL12 in adipocytes. Consequently, this vicious cycle promotes adipose tissue expansion and inflammation. In contrast, genetic or pharmacological inhibition of xCT, mGluR5, or IFN-γ receptor in adipocytes or NK cells combats obesity and hepatic steatosis and improves glucose tolerance in male mice. Our findings posit that adipose glutamate-induced activation of mGluR5 in NK cells is a novel therapeutic target in obesity-related metabolic disorders.

Section: Discussionmentioning

confidence: 99%

xCT-mediated glutamate excretion in white adipocytes stimulates interferon-γ production by natural killer cells in obesity

Shim

et al. 2022

Preprint

“…Notably, at the molecular level, LPS stimulation induces the production of choline acetyltransferase (ChAT) in murine macrophages, leading to intracellular signal transduction mediated by MyD88 [13]. In a recent study conducted by Yingxu Ma et al, it was revealed that cold exposure leads to the activation of β2-ARs in cholinergic adipose macrophages (ChAMs), resulting in an increase in ACh secretion, which, through α2-nAChRs, in turn stimulates beige fat thermogenesis [14]. These findings suggest that the macrophages ChAT expression may exhibit strain, stimuli, tissue, species, and/or immune status-dependent variations, and that ChAT expression levels in macrophages are likely to undergo delayed or dynamically altered changes following stimulation.…”

Section: Cholinergic Macrophages (Myeloid Cells)mentioning

confidence: 99%

Beyond Neurotransmission: The Immunological Mechanism of ACh from The CAIP Perspective

Wang

2024

BIO Web Conf.

Acetylcholine (ACh), traditionally recognized as a neurotransmitter involved in synaptic signaling, has emerged as a crucial player in the immune system, extending beyond its classical functions. Extensive scientific research has shed light on the intricate mechanisms underlying the cholinergic antiinflammatory pathway (CAIP), which plays a pivotal role in regulating immune responses and preserving homeostasis. Primarily mediated by the vagus nerve, this pathway involves the interaction between the nervous and immunological systems. ACh, acting as a key signaling molecule, exerts anti-inflammatory effects by modulating immune cell polarization (encompassing both morphological and functional changes), cytokine production, and signaling pathways. T cells and macrophages, equipped with the cholinergic system, prominently contribute to this immunomodulatory process. Nevertheless, the precise mechanisms governing the CAIP and the specific contribution of ACh in immunological responses remain subjects of ongoing research and debate. This concise review explores the intricate neuro-immune interactions, with a particular focus on the CAIP. Additionally, we delve into the cholinergic system within immune cells, examining the influence of lymphocyte-derived ACh on immunological functioning, thereby illuminating its regulatory role in immune responses and homeostasis maintenance, providing new insights into the development of innovative therapeutic strategies to combat inflammation-related diseases.

“…Numerous published studies emphasize the significant impact of thermogenic fat cell activity on energy expenditure, glucose homeostasis, and cholesterol metabolism [13,35,36,[38][39][40]. Cold exposure is the most well-known stimulus for thermogenesis [24,[41][42][43].…”

Section: The Roles Of Different Types Of Adipose Tissue In Metabolismmentioning

confidence: 99%

“…Although the symptoms of obesity may not be immediately apparent, its long-term consequences are severe. As a key player in various physiological processes, recent studies have reported that obesityrelated metabolic complications are intertwined with multiple mechanisms, including epigenetics [2][3][4][5][6][7][8], immune regulation [9][10][11][12][13], gut microbiota metabolism [14][15][16], aging, and cancer [17][18][19][20][21]. While not all obese individuals develop severe complications, those who are metabolically obese are more prone to metabolic disorders, whereas metabolically healthy obese individuals rarely experience such issues [22].…”

Section: Introductionmentioning

confidence: 99%

Plasticity of Adipose Tissues: Interconversion among White, Brown, and Beige Fat and Its Role in Energy Homeostasis

Peng,

Zhao,

et al. 2024

Biomolecules

Obesity, characterized by the excessive accumulation of adipose tissue, has emerged as a major public health concern worldwide. To develop effective strategies for treating obesity, it is essential to comprehend the biological properties of different adipose tissue types and their respective roles in maintaining energy balance. Adipose tissue serves as a crucial organ for energy storage and metabolism in the human body, with functions extending beyond simple fat storage to encompass the regulation of energy homeostasis and the secretion of endocrine factors. This review provides an overview of the key characteristics, functional differences, and interconversion processes among white adipose tissue (WAT), brown adipose tissue (BAT), and beige adipose tissue. Moreover, it delves into the molecular mechanisms and recent research advancements concerning the browning of WAT, activation of BAT, and whitening of BAT. Although targeting adipose tissue metabolism holds promise as a potential approach for obesity treatment, further investigations are necessary to unravel the intricate biological features of various adipose tissue types and elucidate the molecular pathways governing their interconversion. Such research endeavors will pave the way for the development of more efficient and targeted therapeutic interventions in the fight against obesity.