Loss of ABHD15 Impairs the Anti-lipolytic Action of Insulin by Altering PDE3B Stability and Contributes to Insulin Resistance

Xia, Wenmin; Pessentheiner, Ariane; Hofer, Dina; Amor, Melina; Schreiber, Renate; Schoiswohl, Gabriele; Eichmann, Thomas O.; Walenta, Evelyn; Itariu, Bianca; Prager, Gerhard; Hackl, Hubert; Stulnig, Thomas M.; Kratky, Dagmar; Rülicke, Thomas; Bogner‐Strauß, Juliane Gertrude

doi:10.1016/j.celrep.2018.04.055

Cited by 39 publications

(27 citation statements)

References 57 publications

(87 reference statements)

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“…Therefore, plasma fatty acids were assessed before and 10 min after insulin injection. Insulin significantly suppressed plasma fatty acids by almost 50% in wild type mice (Figure 6B–C), and this effect was significantly impaired in ABHD15 −/− mice (Figure 6B–C), in agreement with previous reports [27]. Notably, both genotypes showed a significant reduction in blood glucose in response to insulin (Figure 5D).…”

Section: Resultssupporting

confidence: 92%

“…Initially described as a novel insulin-regulated phosphoprotein that showed increased expression during adipocyte differentiation [10], ABHD15 was subsequently shown to interact with and stabilize PDE3B [8]. Another group found a role for ABHD15 in adipogenesis [33], and more recently they reported that deletion of ABHD15 in mice resulted in a generalized defect in insulin signaling and action resulting in impaired lipolysis and glucose metabolism [27]. While our studies concur on some aspects, such as the requirement for ABHD15 in insulin mediated suppression of plasma free fatty acids, there are several notable mechanistic differences worthy of mention.…”

Section: Discussionmentioning

confidence: 99%

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ABHD15 regulates adipose tissue lipolysis and hepatic lipid accumulation

Stöckli

Zadoorian

Cooke

et al. 2019

Molecular Metabolism

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Objective Insulin suppresses adipose tissue lipolysis after a meal, playing a key role in metabolic homeostasis. This is mediated via the kinase Akt and its substrate phosphodiesterase 3B (PDE3B). Once phosphorylated and activated, PDE3B hydrolyses cAMP leading to the inactivation of cAMP-dependent protein kinase (PKA) and suppression of lipolysis. However, several gaps have emerged in this model. Here we investigated the role of the PDE3B-interacting protein, α/β-hydrolase ABHD15 in this process. Methods Lipolysis, glucose uptake, and signaling were assessed in ABHD15 knock down and knock out adipocytes and fat explants in response to insulin and/or β-adrenergic receptor agonist. Glucose and fatty acid metabolism were determined in wild type and ABHD15 −/− littermate mice. Results Deletion of ABHD15 in adipocytes resulted in a significant defect in insulin-mediated suppression of lipolysis with no effect on insulin-mediated glucose uptake. ABHD15 played a role in suppressing PKA signaling as phosphorylation of the PKA substrate Perilipin-1 remained elevated in response to insulin upon ABHD15 deletion. ABHD15 −/− mice had normal glucose metabolism but defective fatty acid metabolism: plasma fatty acids were elevated upon fasting and in response to insulin, and this was accompanied by elevated liver triglycerides upon β-adrenergic receptor activation. This is likely due to hyperactive lipolysis as evident by the larger triglyceride depletion in brown adipose tissue in these mice. Finally, ABHD15 protein levels were reduced in adipocytes from mice fed a Western diet, further implicating this protein in metabolic homeostasis. Conclusions Collectively, ABHD15 regulates adipocyte lipolysis and liver lipid accumulation, providing novel therapeutic opportunities for modulating lipid homeostasis in disease.

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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

ABHD15 regulates adipose tissue lipolysis and hepatic lipid accumulation

Stöckli

Zadoorian

Cooke

et al. 2019

Molecular Metabolism

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“…Two low-frequency missense variants in ABHD15, which encodes alpha/beta hydrolase domaincontaining protein 15, were found to be associated with elevated WHRadjBMI. ABHD15 is also highly expressed in adipocytes and has been reported to mediate insulin-induced suppression of lipolysis in adipocytes (32). We also identified a low-frequency variant in a known locus (CALCRL Leu87Pro, 0.1% frequency) associated with lower WHRadjBMI (20.14 SD, P = 1.9 3 10 211 ).…”

Section: Exome-wide Association Study Of Body Fat Distribution In Uk mentioning

confidence: 68%

DNA Sequence Variation in ACVR1C Encoding the Activin Receptor-Like Kinase 7 Influences Body Fat Distribution and Protects Against Type 2 Diabetes

et al. 2018

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A genetic predisposition to higher waist-to-hip ratio adjusted for BMI (WHRadjBMI), a measure of body fat distribution, associates with increased risk for type 2 diabetes. We conducted an exome-wide association study of coding variation in UK Biobank (405,569 individuals) to identify variants that lower WHRadjBMI and protect against type 2 diabetes. We identified four variants in the gene ACVR1C (encoding the activin receptor-like kinase 7 receptor expressed on adipocytes and pancreatic b-cells), which independently associated with reduced WHRadjBMI: Asn150His (20.09 SD, P = 3.4 3 10 217 ), Ile195Thr (20.15 SD, P = 1.0 3 10 29 ), Ile482Val (20.019 SD, P = 1.6 3 10 25 ), and rs72927479 (20.035 SD, P = 2.6 3 10 212 ). Carriers of these variants exhibited reduced percent abdominal fat in DEXA imaging. Pooling across all four variants, a 0.2 SD decrease in WHRadjBMI through ACVR1C was associated with a 30% lower risk of type 2 diabetes (odds ratio [OR] 0.70, 95% CI 0.63, 0.77; P = 5.6 3 10 213 ). In an analysis of exome sequences from 55,516 individuals, carriers of predicted damaging variants in ACVR1C were at 54% lower risk of type 2 diabetes (OR 0.46, 95% CI 0.27, 0.81; P = 0.006). These findings indicate that variants predicted to lead to loss of ACVR1C gene function influence body fat distribution and protect from type 2 diabetes.

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“…This explained the lack of decrease in FFA efflux despite increasing protein kinase A(PKA) activity and phosphorylation levels of hormone-sensitive lipase (HSL). 46 Insulin may also inhibit lipolysis through the regulatory subunit of phosphorylated protein phosphatase-1 (PP-1), which, once activated, rapidly dephosphorylates and deactivates HSL, thereby reducing the lipolysis rate. 47,48 In addition, insulin appears to inhibit lipolysis independently of Akt under certain conditions.…”

Section: Insulin Mechanism Of Action Against Lipolysismentioning

confidence: 99%

<p>Anti-Lipolysis Induced by Insulin in Diverse Pathophysiologic Conditions of Adipose Tissue</p>

Zhao¹,

Wu²,

Rong³

et al. 2020

DMSO

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As an important energy reservoir, adipose tissue maintains lipid balance and regulates energy metabolism. When the body requires energy, adipocytes provide fatty acids to peripheral tissues through lipolysis. Insulin plays an important role in regulating normal fatty acid levels by inhibiting lipolysis. When the morphology of adipose tissue is abnormal, its microenvironment changes and the lipid metabolic balance is disrupted, which seriously impairs insulin sensitivity. As the most sensitive organ to respond to insulin, lipolysis levels in adipose tissue are affected by impaired insulin function, which results in serious metabolic diseases. However, the specific underlying mechanisms of this process have not yet been fully elucidated, and further study is required. The purpose of this review is to discuss the effects of adipose tissue on the anti-lipolysis process triggered by insulin under different conditions. In particular, the functional changes of this process respond to inconsonantly morphological changes of adipose tissue.

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Loss of ABHD15 Impairs the Anti-lipolytic Action of Insulin by Altering PDE3B Stability and Contributes to Insulin Resistance

Cited by 39 publications

References 57 publications

ABHD15 regulates adipose tissue lipolysis and hepatic lipid accumulation

ABHD15 regulates adipose tissue lipolysis and hepatic lipid accumulation

DNA Sequence Variation in ACVR1C Encoding the Activin Receptor-Like Kinase 7 Influences Body Fat Distribution and Protects Against Type 2 Diabetes

<p>Anti-Lipolysis Induced by Insulin in Diverse Pathophysiologic Conditions of Adipose Tissue</p>

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