Deficiency of TNFα Converting Enzyme (TACE/ADAM17) Causes a Lean, Hypermetabolic Phenotype in Mice

Gelling, Richard W.; Yan, Wenbo; Al-Noori, Salwa; Pardini, Aaron W.; Morton, Gregory J.; Ogimoto, Kayoko; Schwartz, Michael W.; Dempsey, Peter J.

doi:10.1210/en.2008-0775

Cited by 70 publications

(76 citation statements)

References 83 publications

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“…Since myostatin-deficient mice did not exhibit hyperphagia characteristic of WT animals with reduced leptin levels (9,26), as well as some hypermetabolic mouse models (1, 9), we hypothesized that sensitivity to leptin in these animals is increased such that relatively low leptin levels provide a leptin signal to the brain of sufficient magnitude to maintain food intake at levels similar to that of normal animals with higher leptin levels. Our finding that the ability of exogenous leptin to reduce body weight and food intake is increased in mice lacking myostatin provides direct evidence in support of this hypothesis, although additional work is needed to determine the relative loss of muscle and fat mass induced by leptin.…”

Section: Discussionmentioning

confidence: 99%

Increased energy expenditure and leptin sensitivity account for low fat mass in myostatin-deficient mice

Choi

Yablonka–Reuveni²,

Kaiyala

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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Choi SJ, Yablonka-Reuveni Z, Kaiyala KJ, Ogimoto K, Schwartz MW, Wisse BE. Increased energy expenditure and leptin sensitivity account for low fat mass in myostatin-deficient mice. Am J Physiol Endocrinol Metab 300: E1031-E1037, 2011. First published March 22, 2011; doi:10.1152/ajpendo.00656.2010.-Myostatin deficiency causes dramatically increased skeletal muscle mass and reduced fat mass. Previously, myostatin-deficient mice were reported to have unexpectedly low total energy expenditure (EE) after normalizing to body mass, and thus, a metabolic cause for low fat mass was discounted. To clarify how myostatin deficiency affects the control of body fat mass and energy balance, we compared rates of oxygen consumption, body composition, and food intake in young myostatindeficient mice relative to wild-type (WT) and heterozygous (HET) controls. We report that after adjusting for total body mass using regression analysis, young myostatin-deficient mice display significantly increased EE relative to both WT (ϩ0.81 Ϯ 0.28 kcal/day, P ϭ 0.004) and HET controls (ϩ0.92 Ϯ 0.31 kcal/day, P ϭ 0.005). Since food intake was not different between groups, increased EE likely accounts for the reduced body fat mass (KO: 8.8 Ϯ 1.1% vs. WT: 14.5 Ϯ 1.3%, P ϭ 0.003) and circulating leptin levels (KO: 0.7 Ϯ 0.2 ng/ml vs. WT: 1.9 Ϯ 0.3 ng/ml, P ϭ 0.008). Interestingly, the observed increase in adjusted EE in myostatin-deficient mice occurred despite dramatically reduced ambulatory activity levels (Ϫ50% vs. WT, P Ͻ 0.05). The absence of hyperphagia together with increased EE in myostatin-deficient mice suggests that increased leptin sensitivity may contribute to their lean phenotype. Indeed, leptin-induced anorexia (KO: Ϫ17 Ϯ 1.2% vs. WT: Ϫ5 Ϯ 0.3%) and weight loss (KO: Ϫ2.2 Ϯ 0.2 g vs. WT: Ϫ1.6 Ϯ 0.1, P Ͻ 0.05) were increased in myostatin-deficient mice compared with WT controls. We conclude that increased EE, together with increased leptin sensitivity, contributes to low fat mass in mice lacking myostatin. energy balance; locomotor activity; body fat; insulin sensitivity MYOSTATIN, a member of the transforming growth factor-␤ family, is a paracrine factor that regulates skeletal muscle size and growth by favoring muscle atrophy and inhibiting anabolic signaling (12, 15). In mice (22) and humans (30), homozygous loss-of-function mutation of the myostatin gene causes a phenotype characterized by dramatic, whole body skeletal muscle hypertrophy and hyperplasia. Initial characterization of the energy homeostasis phenotype of myostatin-null mice revealed unexpected findings, suggesting a role for myostatin in the control of energy balance beyond its effect on skeletal muscle. Mature myostatin-null mice were found to have reduced body fat accumulation with age (23). Because energy expenditure (EE; normalized to body weight or lean body mass) in these animals was decreased relative to wild-type (WT) controls, suggestive of increased metabolic efficiency, the low-body fat phenotype remained unexplained (11, 23). A subsequent, extensive analysi...

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Section: Discussionmentioning

confidence: 99%

Increased energy expenditure and leptin sensitivity account for low fat mass in myostatin-deficient mice

Choi

Yablonka–Reuveni²,

Kaiyala

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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“…Gelling et al also reported a relatively small population of mice lacking functional Tace (Tace ∆Zn/∆Zn ) that survive to adulthood and display markedly increased energy expenditure and a lean phenotype. 11 The target molecules responsible for these phenotypes observed in mice with Tace inactivation remain elusive. Because neither TNF-α nor TNF-α receptors-deficient (p55 -/-p75 -/-) mice exhibit a lean phenotype under HFD feeding, 28 it is probable that the participation of TNF-α-TNF-α receptor signaling pathways might be minimal under the current settings.…”

Section: Discussionmentioning

confidence: 99%

“…Alternatively, previous study using Tace ∆Zn/∆Zn showed alterations in white adipose tissue phenotype displaying features characteristic of brown adipose tissue. 11 Perturbations in sympathetic nervous system outflow to brown adipose tissue might contribute to the hypermetabolic phenotype. However, our mice exhibited no adipose tissue phenotype characteristic of brown adipose tissue, such as increased cellularity and adipocytes with multilocular appearance.…”

Section: Discussionmentioning

confidence: 99%

“…9, 10 Although neither TNF-α-nor TNF-α receptor-deficient mice show significant changes Tace Inactivation Ameliorates Insulin Resistance in body weight (BW) when fed a HFD, mice lacking functional Tace exhibit a lean phenotype and markedly increased energy expenditure, suggesting an important role of Tace in energy homeostasis. 11 To evaluate the pathogenic role of Tace in obesity-induced metabolic disorders, we generated Tace flox/flox /Mx1-Cre mice (TaceMx1) to allow temporal systemic deletion of Tace as previously reported, 12 because Tace-deficient mice die perinatally. 13 The primary aim of this study was to clarify the role of Tace in the pathogenesis of obesity-induced metabolic disorders and energy homeostasis using TaceMx1 transgenic mice.…”

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Tumor Necrosis Factor-.ALPHA. Converting Enzyme Inactivation Ameliorates High-Fat Diet-Induced Insulin Resistance and Altered Energy Homeostasis

Kaneko

Anzai

Horiuchi

et al. 2011

Circ J

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Background: Tumor necrosis factor (TNF)-α, which is released as a soluble form by ectodomain shedding of TNF-α converting enzyme (Tace), is known to play a pivotal role in obesity-induced insulin resistance. The role of Tace in obesity-induced metabolic disorders was to be clarified in this study. Methods and Results:Transgenic mice with temporal systemic Tace deletion (TaceMx1) and their non-transgenic littermates (CON) were fed a standard diet or a high-fat diet (HFD) from 6 weeks of age. The increased body, liver and epididymal adipose tissue (EAT) weights, systolic blood pressure, and fasting glucose and lipid levels and decreased serum adiponectin level 12 weeks after starting a HFD were suppressed by Tace inactivation. A HFD/ TaceMx1 showed ameliorated glucose tolerance and insulin sensitivity compared with HFD/CON. Indirect calorimetry showed that energy expenditure and oxidation of both fat and carbohydrate were higher in HFD/TaceMx1 than HFD/CON. Marked hepatosteatosis, increased triglyceride content and TNF-α expression in liver, and increased adipocyte size, macrophage infiltration and TNF-α and monocyte chemoattractant protein-1 expression in EAT induced by a HFD were attenuated in HFD/TaceMx1. Conclusions:Inactivation of Tace suppressed HFD-induced obesity, insulin resistance, hepatosteatosis and adipose tissue remodeling in association with increased energy expenditure, suggesting an important role of Tace in the development of obesity-induced metabolic disorders. (Circ J 2011; 75: 2482 - 2490

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“…De même, un inhibiteur synthétique d'ADAM17 administré chez des rats hypertendus et insulinorésistants, nourris avec du fructose, mais non obèses, améliore la sensibilité à l'insuline [39]. Les souris déficientes en ADAM17 décrites ci-dessus [19] présentent un phénotype maigre associé à une forte dépense calorique [40]. Une fonction hypothalamique d'ADAM17 contrôlant la balance énergéti-que est évoquée dans ce travail.…”

Section: Revuesunclassified

Les deux visages d’ADAM17 dans l’inflammation

et al. 2009

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La protéolyse de substrats ancrés à la surface cellulaire (shedding) permet aux cellules de libérer des média-teurs et de contrôler leurs interactions avec la matrice extracellulaire et les ligands, qu'ils soient solubles ou associés aux cellules. Ce processus implique des métal-loprotéinases qui clivent la partie extracellulaire de molécules transmembranaires (cytokines, récepteurs, molécules d'adhésion et facteurs de croissance). Les métalloprotéinases se répartissent en plusieurs classes : (1) les métalloprotéinases matricielles (MMP) sécrétées (matrilysines, collagénases, gélatinases, stromélysi-nes) ; (2) les métalloprotéinases associées à la membrane par un domaine transmembranaire ou un ancrage GPI (glycosylphosphatidyl inositol) ou membrane-type MMP ; (3) les ADAM (a disintegrin and metalloprotease) qui sont transmembranaires, et (4) les ADAM-TS (TS pour thrombospondin motif) qui sont des ADAM sécrétées. Nous focaliserons cette revue sur ADAM17, la plus étu-diée des ADAM, et son implication dans deux pathologies inflammatoires, l'athérosclérose et l'obésité. L'espace limité ne nous permet pas d'aborder le rôle de ADAM17 dans d'autres maladies comme l'arthrite rhumatoïde et le cancer (pour revues, voir [1-3]). ADAM17 : présentation généraleLes ADAM (environ 40 ont été décrites) appartiennent à la superfamille des métalloprotéinases à zinc [2,4].Quatre inhibiteurs protéiques endogènes distincts, les TIMP (tissue inhibitor of metalloproteinase), régulent l'activité de la plupart des ADAM. Les différents domaines structuraux qui composent les ADAM confèrent à certaines d'entre elles des fonctions distinctes dont le clivage protéolytique, l'adhésion et la signalisation. Les ADAM régulent des fonctions cellulaires telles que la prolifération, la fusion cellulaire, et les interactions cellule-matrice et cellule-cellule, ce qui les implique dans différents processus biologiques comme la reproduction et le développement [5]. Leurs rôles dans l'arthrite rhumatoïde, le cancer, l'asthme, l'athéros-clérose, l'obésité et le diabète sont de mieux en mieux documentés. Parmi les ADAM, c'est probablement à l'étude de ADAM17 qu'ont été consacrés le plus de travaux, depuis le clonage de son gène en 1997 [6,7]. Cette enzyme a été initialement caractérisée comme responsable du clivage du TNFα (tumour necrosis factor), d'où sa dénomination de TNF alpha converting enzyme (TACE), transformant le TNF transmembranaire (tmTNF) de 26 kDa en une forme soluble de 17 kDa (sTNF). Les souris déficientes en activité ADAM17 par mutation du site actif meurent très pré-maturément, alors que les souris déficientes en TNF sont viables, suggérant qu'ADAM17 clive d'autres molécules que le seul TNF. En effet, l'identification d'autres substrats clivés par ADAM17, comme les ligands de l'EGFR (epidermal growth factor receptor), souligne son rôle > La métalloprotéase ADAM17 (a disintegrin and metalloprotease17) est une protéine transmembranaire de type I, responsable de la protéolyse de nombreux substrats à la surface cellulaire. Sa structure, sa bi...

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Deficiency of TNFα Converting Enzyme (TACE/ADAM17) Causes a Lean, Hypermetabolic Phenotype in Mice

Cited by 70 publications

References 83 publications

Increased energy expenditure and leptin sensitivity account for low fat mass in myostatin-deficient mice

Increased energy expenditure and leptin sensitivity account for low fat mass in myostatin-deficient mice

Tumor Necrosis Factor-.ALPHA. Converting Enzyme Inactivation Ameliorates High-Fat Diet-Induced Insulin Resistance and Altered Energy Homeostasis

Les deux visages d’ADAM17 dans l’inflammation

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