bims-aditis 2022-02-27 papers

Issue of 2022–02–27
four papers selected by
Matthew C. Sinton, University of Glasgow

Int Rev Immunol. 2022 Feb 25. 1-11

Adipose tissue regulatory T cells: differentiation and function.

Allen N Fooks, Lisa Y Beppu, Adolfo B Frias, Louise M D'Cruz.

Rising obesity levels, worldwide, are resulting in substantial increases in cardiovascular disease, diabetes, kidney disease, musculoskeletal disorders, and certain cancers, and obesity-associated illnesses are estimated to cause ∼4 million deaths worldwide per year. A common theme in this disease epidemic is the chronic systemic inflammation that accompanies obesity. CD4+ Foxp3+ regulatory T cells residing in visceral adipose tissues (VAT Tregs) are a unique immune cell population that play essential functions in restricting obesity-associated systemic inflammation through regulation of adipose tissue homeostasis. The distinct transcriptional program that defines VAT Tregs has been described, but directly linking VAT Treg differentiation and function to improving insulin sensitivity has proven more complex. Here we review new findings which have clarified how VAT Tregs differentiate, and how distinct VAT Treg subsets regulate VAT homeostasis, energy expenditure, and insulin sensitivity.

Keywords: Treg; adipose tissue; cytokine; thermogenesis

DOI: https://doi.org/10.1080/08830185.2022.2044808

Proc Natl Acad Sci U S A. 2022 Mar 01. pii: e2112840119. [Epub ahead of print]119(9):

An immune-sympathetic neuron communication axis guides adipose tissue browning in cancer-associated cachexia.

Hao Xie, Christoph Heier, Xia Meng, Latifa Bakiri, Isabella Pototschnig, Zhiyuan Tang, Silvia Schauer, Vanessa J Baumgartner, Gernot F Grabner, Gernot Schabbauer, Heimo Wolinski, Graham R Robertson, Gerald Hoefler, Wenwen Zeng, Erwin F Wagner, Martina Schweiger, Rudolf Zechner.

Cancer-associated cachexia (CAC) is a hypermetabolic syndrome characterized by unintended weight loss due to the atrophy of adipose tissue and skeletal muscle. A phenotypic switch from white to beige adipocytes, a phenomenon called browning, accelerates CAC by increasing the dissipation of energy as heat. Addressing the mechanisms of white adipose tissue (WAT) browning in CAC, we now show that cachexigenic tumors activate type 2 immunity in cachectic WAT, generating a neuroprotective environment that increases peripheral sympathetic activity. Increased sympathetic activation, in turn, results in increased neuronal catecholamine synthesis and secretion, β-adrenergic activation of adipocytes, and induction of WAT browning. Two genetic mouse models validated this progression of events. 1) Interleukin-4 receptor deficiency impeded the alternative activation of macrophages, reduced sympathetic activity, and restrained WAT browning, and 2) reduced catecholamine synthesis in peripheral dopamine β-hydroxylase (DBH)-deficient mice prevented cancer-induced WAT browning and adipose atrophy. Targeting the intraadipose macrophage-sympathetic neuron cross-talk represents a promising therapeutic approach to ameliorate cachexia in cancer patients.

Keywords: adipose tissue; browning; cancer cachexia; immunometabolism; macrophage

DOI: https://doi.org/10.1073/pnas.2112840119

Theranostics. 2022 ;12(4): 1589-1606

PPAR-γ integrates obesity and adipocyte clock through epigenetic regulation of Bmal1.

Shuai Wang, Yanke Lin, Lu Gao, Zemin Yang, Jingpan Lin, Shujing Ren, Feng Li, Jing Chen, Zhigang Wang, Zhiyong Dong, Pinghua Sun, Baojian Wu.

While growing evidence suggests that circadian clock and obesity are intertwined, the underlying mechanism is poorly understood. Here, we investigate how circadian clock is linked to obesity. Methods: Metabolomics profiling of WAT (white adipose tissue) samples was performed to identify the metabolites altered in obese model. mRNA levels were analyzed by qPCR assays. Proteins were detected by immunoblotting, immunofluorescence and ELISA. ChIP and luciferase reporter assays were used to investigate epigenetic and transcriptional regulation. Results: Obesity causes perturbance of circadian clock in WAT in mice and humans, particularly, BMAL1 is markedly reduced. Metabolomic analysis reveals reduced glutamine and methionine in obese WAT. Glutamine metabolism contributes to production of acetyl-CoA, whereas methionine metabolism generates S-adenosyl methionine (SAM). Acetyl-CoA and SAM are the substrates for histone acetylation and methylation, respectively. Reduced glutamine and methionine in obese WAT are associated with decreased H3K27ac and H3K4me3 at Bmal1 promoter. Consistently, glutamine or methionine administration in vitro and in vivo increases H3K27ac or H3K4me3, promoting Bmal1 transcription and expression. A screen of transport and metabolic genes identifies downregulation of the uptake transporter SLC1A5 as a cause of reduced glutamine or methionine in obese WAT. Moreover, we observe impaired expression of PPAR-γ in obese WAT. PPAR-γ trans-activates Slc1a5 via direct binding to a response element in promoter. Conclusion: Impaired PPAR-γ in obesity provokes downregulation of SLC1A5 and reductions in adipocyte uptake of glutamine and methionine (two epigenetic modulators), leading to disruption of Bmal1. Therefore, PPAR-γ integrates obesity and adipocyte clock, promoting a vicious cycle between circadian disruption and obesity development.

Keywords: BMAL1; PPAR-γ; SLC1A5; circadian clock; obesity

DOI: https://doi.org/10.7150/thno.69054

Front Cell Infect Microbiol. 2022 ;12 824494

Causative Agents of American Tegumentary Leishmaniasis Are Able to Infect 3T3-L1 Adipocytes In Vitro.

Bruno Mendes, Karen Minori, Silvio R Consonni, Norma W Andrews, Danilo C Miguel.

Although macrophages have long been considered key players in the course of Leishmania infections, other non-professional phagocytes have lately been shown to maintain low levels of the parasite in safe intracellular niches. Recently, it was demonstrated that the adipose tissue is capable of harboring Old World L. (L.) infantum in mice. However, there is no evidence of experimental adipocyte infection with New World Leishmania species so far. In addition, it was not known whether adipocytes would be permissive for formation of the unique, large and communal parasitophorous vacuoles that are typical of L. (L.) amazonensis in macrophages. Here we evaluated the ability of L. (L.) amazonensis and L. (V.) braziliensis promastigotes and amastigotes to infect 3T3-L1 fibroblast-derived adipocytes (3T3-Ad) using light and transmission electron microscopy. Our results indicate that amastigotes and promastigotes of both species were capable of infecting and surviving inside pre- and fully differentiated 3T3-Ad for up to 144 h. Importantly, L. (L.) amazonensis amastigotes resided in large communal parasitophorous vacuoles in pre-adipocytes, which appeared to be compressed between large lipid droplets in mature adipocytes. In parallel, individual L. (V.) braziliensis amastigotes were detected in single vacuoles 144 h post-infection. We conclude that 3T3-Ad may constitute an environment that supports low loads of viable parasites perhaps contributing to parasite maintenance, since amastigotes of both species recovered from these cells differentiated into replicative promastigotes. Our findings shed light on the potential of a new host cell model that can be relevant to the persistence of New World Leishmania species.

Keywords: 3T3-L1; Leishmania; adipocyte; infection; microscopy

DOI: https://doi.org/10.3389/fcimb.2022.824494