Rab4b Deficiency in T Cells Promotes Adipose Treg/Th17 Imbalance, Adipose Tissue Dysfunction, and Insulin Resistance

Gilleron, Jérôme; Bouget, Gwennaelle; Ivanov, Stoyan; Meziat, Cindy; Ceppo, Franck; Vergoni, Bastien; Djedaini, Mansour; Soprani, Antoine; Dumas, Karine; Jacquel, Arnaud; Yvan‐Charvet, Laurent; Venteclef, Nicolas; Tanti, Jean‐François; Cormont, Mireille

doi:10.1016/j.celrep.2018.11.083

Cited by 38 publications

(30 citation statements)

References 57 publications

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“…Whole‐body knockout mice for Rab4a and Rab4b display a reduction in circulating triglycerides and an increase in their total body fat mass, respectively, indicating a function of Rab4 in lipid metabolism (IMPC). The phenotype of Rab4b knockout mice could be in part due to the key role of Rab4b in adipose tissue T cells, as was recently demonstrated . After passing through early endosomes, GLUT4 traffics through the endosomal recycling compartment, involving Rab11.…”

Section: Regulation Of Glucose and Lipid Metabolism Through The Endosmentioning

confidence: 84%

Metabolic regulation through the endosomal system

Gilleron

Gerdes

Zeigerer

2019

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The endosomal system plays an essential role in cell homeostasis by controlling cellular signaling, nutrient sensing, cell polarity and cell migration. However, its place in the regulation of tissue, organ and whole body physiology is less well understood. Recent studies have revealed an important role for the endosomal system in regulating glucose and lipid homeostasis, with implications for metabolic disorders such as type 2 diabetes, hypercholesterolemia and non‐alcoholic fatty liver disease. By taking insights from in vitro studies of endocytosis and exploring their effects on metabolism, we can begin to connect the fields of endosomal transport and metabolic homeostasis. In this review, we explore current understanding of how the endosomal system influences the systemic regulation of glucose and lipid metabolism in mice and humans. We highlight exciting new insights that help translate findings from single cells to a wider physiological level and open up new directions for endosomal research.

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Section: Regulation Of Glucose and Lipid Metabolism Through The Endosmentioning

confidence: 84%

Metabolic regulation through the endosomal system

Gilleron

Gerdes

Zeigerer

2019

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“…The total count ranged from 3275 to 7052 cells per condition (n≥4 mice per group). (F) Box-whiskers (min-max) of the number of adipocytes which was estimated using the mathematical equation developed by Jo et al[32], as previously described in [20]. g , Table showing the differentially expressed genes (DEGs) in WD1 and WD5 perigonadal white adipose tissue.…”

Section: Resultsmentioning

confidence: 99%

“…The aforementioned modulations of white adipose tissue in WD generations shed light on the possible exacerbation of obesity-associated pathologies (such as insulin resistance (and subsequently type-II diabetes) and nonalcoholic fatty liver disease) [20]. To check this hypothesis, several metabolic risk parameters related to these pathologies were analyzed in WD-fed mice ( Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

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Paternal multigenerational exposure to an obesogenic diet drives epigenetic predisposition to metabolic disorders

Raad¹,

Serra

Martin

et al. 2020

Preprint

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20Obesity is a growing societal scourge responsible for approximately 4 million deaths 21 worldwide. Recent studies have uncovered that paternal excessive weight induced by an 22 unbalanced diet affects the metabolic health of offspring. These reports mainly employed 23 single-generation male exposure. However, the consequences of multigenerational 24 unbalanced diet feeding on the metabolic health of progeny remain largely unknown. Here, we 25 show that maintaining paternal western diet feeding for five consecutive generations in mice 26 induces a gradual enhancement in fat mass and related metabolic diseases over generations. 27Strikingly, chow-diet-fed progenies from these multigenerational western-diet-fed males 28 develop a "healthy" overweight phenotype that is not reversed after 4 subsequent generations. 29Mechanistically, sperm RNA microinjection experiments into zygotes suggest that sperm 30 RNAs are sufficient for establishment but not for long-term maintenance of epigenetic 31 inheritance of metabolic pathologies. Progressive and permanent metabolic deregulation 32 induced by successive paternal western-diet-fed generations may contribute to the worldwide 33 epidemic of metabolic diseases. 35 Introduction 36Nongenetic inheritance of newly acquired phenotypes is a new concept in biology whereby 37 changes induced by specific environmental cues in parents (mothers and/or fathers) can be 38 transmitted to the next generation [1][2][3]. This process is evolutionarily conserved and has been 39 described from worms to humans [4][5][6][7]. The fact that environmental cues have the potential to 40 modify the molecular hereditary information carried by the spermatozoa demonstrates that the 41 environmentally induced epigenetic modifications [8][8] are not erased through the epigenetic 42 reprogramming process, causing them to be inherited by the next generations [9, 10]. Although 43 the role of epigenetic modifications such as DNA methylation [9, 11, 12] and chromatin 44 modification [13, 14] cannot be excluded in this process, independent experimental data 45 strongly evoke the central role of sperm RNA as a vector of paternal intergenerational 46 epigenetic inheritance of, at least, environmentally induced metabolic pathologies [1, 3, 15].47 Unlike genetic inheritance, environmentally induced epigenetic alterations are reversible, 48 enabling the loss of previously acquired characteristics [16]. Although environmental changes 49 might persist over several generations, most reports have been based on the maintenance of 50 paternal environmental cues for just one generation [17]. This is particularly true for certain 51 lifestyle habits, such as eating high-fat and high-sugar junk food, also called a Western diet 52 (WD). Thus, although people around the world may face multigenerational unbalanced 53 nutrition, there have been limited studies on its effects on the metabolic health of the progeny. 54Herein, we studied the impact of the paternal maintenance of an unhealthy WD for multiple 55 generations on the me...

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“…25 In addition to these factors, Rab4-B, a small GTPase controlling endocytic trafficking, is reduced in VAT T cells from obese individuals and may also contribute to the reduction in VAT Tregs during obesity. 48 One common caveat of most of these obesity studies has been that they all focus on either mice fed HFD long-term (>8-20 weeks) or genetically obese mice, so only a late snapshot is taken. We still lack a comprehensive view of the exact kinetics of VAT Tregs, their transcriptional changes, and modulations of local environmental factors during the onset, progression, and late phases of obesity, which can reflect distinct physiological or pathological processes (eg, adipocyte differentiation and expansion, hypoxia, endoplasmic reticulum and reactive oxygen species stress, and fibrosis).…”

Section: Sex and Depotmentioning

confidence: 99%

Visceral adipose tissue Tregs and the cells that nurture them

Spallanzani

Mathis

2020

Immunological Reviews

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Visceral adipose tissue (VAT) is a primary site for storage of excess energy, but it also serves as an important endocrine organ that impacts organismal metabolism. Chronic, low-grade inflammation of VAT, and eventually systemically, is one of the major drivers of obesity-associated insulin resistance and metabolic abnormalities. A unique population of regulatory T cells (Tregs), with a distinct transcriptional profile and antigen receptor repertoire resides in VAT, keeps inflammation in check and regulates organismal metabolism. Accumulation of these cells depends on interactions with other local immunocytes and, importantly, subtypes of VAT mesenchymal stromal cells (VmSCs) that are either immunomodulators or adipogenic. We summarize our current understanding of the phenotype, function, dependencies, derivation, and modulations of VAT Tregs, and review the heterogeneity and regulation of VmSCs as well as their cross talk with VAT Tregs. Lastly, we discuss imperative questions remaining to be answered. K E Y W O R D Sadipose tissue obesity, IL-33, immunometabolism, mesenchymal stromal cells, Treg cells

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Rab4b Deficiency in T Cells Promotes Adipose Treg/Th17 Imbalance, Adipose Tissue Dysfunction, and Insulin Resistance

Abstract: Gilleron et al. show that Rab4b expression is decreased in adipose T cells during obesity in mice and humans. They reveal that Rab4b in T cells is critical for the control of adipose tissue remodeling and insulin sensitivity by regulating the adipose Th17/Treg balance.

Cited by 38 publications

References 57 publications

Metabolic regulation through the endosomal system

Metabolic regulation through the endosomal system

Paternal multigenerational exposure to an obesogenic diet drives epigenetic predisposition to metabolic disorders

Visceral adipose tissue Tregs and the cells that nurture them

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