Semaphorin 3C is a novel adipokine linked to extracellular matrix composition

Mejhert, Niklas; Wilfling, Florian; Esteve, Daniel; Galitzky, Jean; Pellegrinelli, Vanessa; Kolditz, Catherine Ines; Viguerie, Nathalie; Tordjman, Joan; Näslund, Erik; Trayhurn, Paul; Lacasa, Danièle; Dahlman, Ingrid; Štich, Vladimír; Lång, Pernilla; Langin, Dominique; Bouloumié, Anne; Clément, Karine; Rydén, Mikael

doi:10.1007/s00125-013-2931-z

Cited by 32 publications

(28 citation statements)

References 47 publications

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“…interleukin 7 receptor, Il7r ) (16) and fibrotic markers (e.g. collagen type VIII alpha 1 chain, Col8a1; semaphorin 3C, Sema3c ) (17,18), and changes in extracellular matrix components (e.g. matrix metallopeptidase 12, Mmp12; procollagen c-endopeptidase enhancer, Pcolce ) (19,20) and cytokines (e.g.…”

Section: Resultsmentioning

confidence: 99%

“…Il7r, which was found to be one of the highest ranking genes in the white adipose tissue inflammatory response pathway (40), decreases expression between 20 and 30 weeks of age in high fat-fed SM/J brown adipose. Col8a1 and Sema3C are both associated with adipose tissue fibrosis (17,41). Increased adipose tissue fibrosis is a signature of dysfunctional adipose and is associated with impaired glucose homeostasis and insulin resistance (18).…”

Section: Discussionmentioning

confidence: 99%

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Brown adipose expansion and remission of glycemic dysfunction in obese SM/J mice

Carson

Macias-Velasco

Gunawardana

et al. 2019

Preprint

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52Disruption of glucose homeostasis increases the risk of type II diabetes, cardiovascular disease, stroke, 53 and cancer. We leverage a novel rodent model, the SM/J mouse, to understand glycemic control in 54 obesity. On a high fat diet, obese SM/J mice initially develop impaired glucose tolerance and elevated 55 fasting glucose. Strikingly, their glycemic dysfunction resolves by 30 weeks of age despite persistence of 56 obesity. A prominent phenotype is that they dramatically expand their brown adipose depots as they 57 resolve glycemic dysfunction. This occurs naturally and spontaneously on a high fat diet, with no 58 temperature or genetic manipulation. When the brown adipose depot is removed from normoglycemic 59 obese mice, fasting blood glucose and glucose tolerance revert to unhealthy levels, and animals become 60 insulin resistant. We identified 267 genes whose expression changes in the brown adipose when the 61 mice resolve their unhealthy glycemic parameters, and find the expanded tissue has a 'healthier' 62 expression profile of cytokines and extracellular matrix genes. We describe morphological, physiological, 63 and transcriptomic changes that occur during the unique brown adipose expansion and remission of 64 glycemic dysfunction in obese SM/J mice. Understanding this phenomenon in mice will open the door for 65 innovative therapies aimed at improving glycemic control in obesity.66 67 Significance Statement 68 Some obese individuals maintain normal glycemic control. Despite being obese, these individuals 69 have low risk for metabolic complications, including type-II diabetes. If we better understood why some 70 obese people maintain normoglycemia then we might develop new approaches for treating metabolic 71 complications associated with obesity. However, the causative factors underlying glycemic control in 72 obesity remain unknown. We discovered that, despite persistence of the obese state, SM/J mice enter 73 into diabetic remission: returning to normoglycemia and reestablishing glucose tolerance and improving 74 insulin sensitivity. A prominent phenotype is that they dramatically expand their brown adipose depots as 75 they resolve glycemic dysfunction. Understanding this phenomenon in mice will open the door for 76 innovative therapies aimed at improving glycemic control in obesity. 78An estimated 10-30% of obese individuals maintain glycemic control and some longitudinal 79 studies suggest their risk of developing type II diabetes is no greater than matched lean individuals (1). 80No causative factors underlying glycemic control in obesity have been discovered, however the strongest 81 predictors of impaired glycemic control in obesity are increased visceral fat mass and adipose tissue 82 dysfunction (2,3). Thus research efforts have focused on understanding the genetic and physiological 83 mechanisms of action of adipose. Recent research reveals that brown adipose activity is associated with 84 anti-diabetic properties. Cold exposure in both obese and lean individuals causes increased uptake...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Brown adipose expansion and remission of glycemic dysfunction in obese SM/J mice

Carson

Macias-Velasco

Gunawardana

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…Western blot was performed as described previously (Mejhert et al, 2013). Primary antibodies were PLIN1 (Progen, Heidelberg, Germany), LIPE (Cell Signalling Technologies, Beverly, MA) and βactin (Sigma-Aldrich).…”

Section: Methodsmentioning

confidence: 99%

Early B Cell Factor 1 Regulates Adipocyte Morphology and Lipolysis in White Adipose Tissue

et al. 2014

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Summary White adipose tissue (WAT) morphology characterized by hypertrophy (i.e. fewer but larger adipocytes) associates with increased adipose inflammation, lipolysis, insulin resistance and risk of diabetes. However, the causal relationships and the mechanisms controlling WAT morphology are unclear. Herein, we identified EBF1 as an adipocyte-expressed transcription factor with decreased expression/activity in WAT hypertrophy. In human adipocytes, the regulatory targets of EBF1 were enriched for genes controlling lipolysis and adipocyte morphology/differentiation and in both humans and murine models, reduced EBF1 levels associated with increased lipolysis and adipose hypertrophy. Although EBF1 did not affect adipose inflammation, TNFα reduced EBF1 gene expression. High fat diet-intervention in Ebf1+/− mice resulted in more pronounced WAT hypertrophy and attenuated insulin sensitivity compared with wild-type littermate controls. We conclude that EBF1 is an important regulator of adipose morphology and fat cell lipolysis and may constitute a link between WAT inflammation, altered lipid metabolism, adipose hypertrophy and insulin resistance.

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“…We obtained eight mutant lines generated by the ZMP (Table 1) (16). The eight ZMP mutants were selected as candidate regulators of adiposity based on published experimental evidence or by genomewide association studies (28)(29)(30)(31)(32)(33)(34)(35). Heterozygous carriers from the ZMP mutants were intercrossed, the offspring was raised to 30 dpf, and then Nile Red was used to visualize AT levels (Fig.…”

Section: Identification Of Nrp2b As a Novel Gene Implicated In Zebrafmentioning

confidence: 99%

Deep phenotyping in zebrafish reveals genetic and diet-induced adiposity changes that may inform disease risk

Minchin

Scahill

Staudt

et al. 2018

Journal of Lipid Research

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The regional distribution of adipose tissues is implicated in a wide range of diseases. For example, proportional increases in visceral adipose tissue increase the risk for insulin resistance, diabetes, and CVD. Zebrafish offer a tractable model system by which to obtain unbiased and quantitative phenotypic information on regional adiposity, and deep phenotyping can explore complex disease-related adiposity traits. To facilitate deep phenotyping of zebrafish adiposity traits, we used pairwise correlations between 67 adiposity traits to generate stage-specific adiposity profiles that describe changing adiposity patterns and relationships during growth. Linear discriminant analysis classified individual fish according to an adiposity profile with 87.5% accuracy. Deep phenotyping of eight previously uncharacterized zebrafish mutants identified as a novel gene that alters adipose distribution. When we applied deep phenotyping to identify changes in adiposity during diet manipulations, zebrafish that underwent food restriction and refeeding had widespread adiposity changes when compared with continuously fed, equivalently sized control animals. In particular, internal adipose tissues (e.g., visceral adipose) exhibited a reduced capacity to replenish lipid following food restriction. Together, these results in zebrafish establish a new deep phenotyping technique as an unbiased and quantitative method to help uncover new relationships between genotype, diet, and adiposity.

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Semaphorin 3C is a novel adipokine linked to extracellular matrix composition

Cited by 32 publications

References 47 publications

Brown adipose expansion and remission of glycemic dysfunction in obese SM/J mice

Brown adipose expansion and remission of glycemic dysfunction in obese SM/J mice

Early B Cell Factor 1 Regulates Adipocyte Morphology and Lipolysis in White Adipose Tissue

Deep phenotyping in zebrafish reveals genetic and diet-induced adiposity changes that may inform disease risk

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