Fatty acid-inducible ANGPTL4 governs lipid metabolic response to exercise

Catoire, Milène; Alex, Sheril; Paraskevopulos, Nicolas; Mattijssen, Frits; Gogh, Inkie Evers-van; Schaart, Gert; Jeppesen, Jacob; Kneppers, Anita; Mensink, Marco; Voshol, Peter J.; Olivecrona, Gunilla; Tan, Nguan Soon; Hesselink, Matthijs K. C.; Berbée, Jimmy F.P.; Rensen, Patrick C.N.; Kalkhoven, Eric; Schrauwen, Patrick; Kersten, Sander

doi:10.1073/pnas.1400889111

Cited by 121 publications

(170 citation statements)

References 53 publications

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“…Glucagon plays an important role in the pathophysiology of type 2 diabetes. We describe a circuit connecting α-cells with Angptl4, a secreted LPL inhibitor expressed in the periphery that is regulated by exercise, the gut microbiota, feeding, and during diabetes (27,45,52). Our study highlights the role of Angptl4 in inducing α-cell proliferation and its importance in the compensatory hyperglucagonemia following treatment with GRA.…”

Section: Discussionmentioning

confidence: 92%

Angptl4 links α-cell proliferation following glucagon receptor inhibition with adipose tissue triglyceride metabolism

Ben‐Zvi

Barrandon

Hadley

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Type 2 diabetes is characterized by a reduction in insulin function and an increase in glucagon activity that together result in hyperglycemia. Glucagon receptor antagonists have been developed as drugs for diabetes; however, they often increase glucagon plasma levels and induce the proliferation of glucagon-secreting α-cells. We find that the secreted protein Angiopoietin-like 4 (Angptl4) is up-regulated via Pparγ activation in white adipose tissue and plasma following an acute treatment with a glucagon receptor antagonist. Induction of adipose angptl4 and Angptl4 supplementation promote α-cell proliferation specifically. Finally, glucagon receptor antagonist improves glycemia in diet-induced obese angptl4 knockout mice without increasing glucagon levels or α-cell proliferation, underscoring the importance of this protein. Overall, we demonstrate that triglyceride metabolism in adipose tissue regulates α-cells in the endocrine pancreas.

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Section: Discussionmentioning

confidence: 92%

Angptl4 links α-cell proliferation following glucagon receptor inhibition with adipose tissue triglyceride metabolism

Ben‐Zvi

Barrandon

Hadley

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…The therapy is typically used in patients who have moderate emphysema (FEV 1 30-65% predicted) and is usually continued indefinitely. Clinical studies demonstrate that A1AT therapy reverses the biochemical abnormalities of the A1AT protein in serum and lung fluid, and reverses the decline in lung density [29,30,31]. It has been shown that the specific A1AT preparation used in our patients (Prolastin®) contains significant quantities of fatty acids.…”

Section: Discussionmentioning

confidence: 99%

“…angptl4 is a potent inhibitor of the lipoprotein lipase (LPL), an enzyme hydrolysing triglycerides [30]. By coordinating lipid uptake in exercising and non-exercising muscles, angptl4 seems to play an important role in LPL-dependent clearance of triglycerides in skeletal muscle, particularly during acute exercise, and potentially contributes in maintaining oxidative muscle fibre expression [31]. Hence, the decreased activity of LPL in human skeletal muscle may blunt the expression of peroxisome proliferator-activated receptor (PPAR), which interacts with PGC1α and regulates oxidative fibre expression and mitochondrial biogenesis [28].…”

Section: Discussionmentioning

confidence: 99%

Different Training-Induced Skeletal Muscle Adaptations in COPD Patients with and without Alpha-1 Antitrypsin Deficiency

et al. 2016

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Background: Pulmonary rehabilitation (PR) improves oxidative capacity of peripheral muscles in patients with chronic obstructive pulmonary disease (COPD). The exercise-induced oxidative skeletal muscle adaptation in COPD patients with inherited alpha-1 antitrypsin deficiency (A1ATD) has not been studied. Objectives: To compare PR effects on skeletal muscle adaptation in COPD patients with and without A1ATD. Methods: Nine COPD patients with A1ATD (genotype PiZZ, 6 receiving A1AT augmentation therapy), and 10 ‘usual' COPD patients (genotype PiMM) performed an incremental cycling test and underwent musculus vastus lateralis biopsies before and after a 3-week PR program including exercise training. Results: PiZZ and PiMM patients improved peak work rate following PR (+9 ± 11 W, p < 0.05, and +18 ± 9 W, p < 0.001, between-group difference p < 0.05). PiMM patients increased fibre type I (+8.1%), reduced fibre type IIA (-2.1%) and hybrid fibre type IIA/IIX proportion (-3.9%). Following PR, PiMM patients also raised mitochondrial signalling proteins PGC-1α (4.5-fold), and TFAM (6.4-fold). PiZZ patients had no change in fibre type I but showed a shift of type IIA/IIX (-8.8%) towards fibre type IIA distribution (+8.9%). The capillary to fibre ratio increased by 28% (p < 0.05) in PiZZ, whereas no change was observed in PiMM patients. Linear regression analysis revealed that diffusion capacity and A1AT therapy are predictor variables for myofibre type I response to PR (r² = 0.684, p < 0.01). Conclusions: Following a 3-week PR with comparable training modalities, PiMM but not PiZZ patients increased the oxidative myofibre type I proportion. This skeletal muscle adaptation pattern suggests better improvement of exercise capacity in PiMM than in PiZZ patients with COPD.

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“…Whereas insulin regulates basal LpL expression, a number of other proteins regulate LpL activity (38). As one example, when exercising muscle is compared with nonexercising muscle (e.g., single-leg cycling), there is a PPARδ-regulated induction of angiopoietin like-4 (ANGPLT4, an inhibitor of LpL) in the nonexercising muscle matched with a concurrent AMPK-mediated suppression of ANGPLT4 in the exercising muscle (39). Thus, coordination of LpL activity channels lipids to metabolically active sites.…”

mentioning

confidence: 99%

The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux

Samuel¹,

Shulman²

2016

Journal of Clinical Investigation

1,016

819

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In most natural habitats, calorie availability is scarce and unpredictable, necessitating the evolution of systems for the efficient storage and utilization of energy. But in our modern, mechanized society, caloric demands are minimized, while highly palatable, calorie-dense foods and beverages are readily available. These changes have fostered the current pandemic of obesity and comorbid conditions of nonalcoholic fatty liver disease (NAFLD), atherosclerosis, and type 2 diabetes (T2D). Insulin resistance is a common feature of all these diseases, and much effort has been invested in delineating the pathogenesis of insulin resistance. We will first review the role of insulin and nutrients (specifically glucose and fatty acids) in nutrient storage ( Figure 1) and then use this framework to explore the various defects that give rise to insulin resistance and T2D (Figure 2). Postprandial hepatic glucose and lipid metabolismThe simple act of eating rapidly shifts hepatic glucose metabolism from glucose production to glucose storage, a complex transition regulated by multiple factors including nutrients, alterations in pancreatic and enteric hormones, and neural regulation. Insulin is a crucial regulator of this transition, primarily by activating glycogen synthase (1). The importance of insulin is seen in patients with type 1 diabetes (T1D), who only synthesize one-third the amount of hepatic glycogen as control subjects after a mixed meal (2). Yet, hyperinsulinemia, in the absence of hyperglycemia, promotes hepatic glycogen cycling with minimal net hepatic glycogen synthesis (1). And hyperglycemia, without hyperinsulinemia, inhibits hepatic glycogenolysis via glucose-mediated inhibition of glycogen phosphorylase (3), with minimal net hepatic glycogen synthesis (1). The combination of hyperinsulinemia and hyperglycemia maximizes net hepatic glycogen synthesis (1). Other nutrients further optimize net hepatic glycogen synthesis, such as activation of glucokinase by catalytic quantities of fructose (4).Hepatic insulin action requires a coordinated relay of intracellular signals (Figure 1 and ref. 5). Insulin activates the insulin receptor tyrosine kinase (IRTK), with subsequent activation of kinases including 3-phosphoinositide-dependent kinase-1 (PDK1) and mTORC2 (6), which converge on Akt phosphorylation (6-8). The pattern of insulin delivery may also impact Akt phosphorylation, with pulsatile portal delivery (which better mimics physiology) leading to greater activation than continuous, fixed insulin delivery (9). Activation of Akt is the integral result of multiple inputs to regulate hepatic glucose and lipid metabolism. This model has been used to explain how insulin suppresses hepatic glucose production via (i) lowering expression of gluconeogenic enzymes via phosphorylation and nuclear exclusion of FOXO1 and (ii) inactivation of glycogen synthase kinase 3β (GSK3β), which permits the activation of glycogen synthase.Recent studies challenge the primacy of the Akt/GSK3β/ glycogen synthase branch in the regulation ...

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Fatty acid-inducible ANGPTL4 governs lipid metabolic response to exercise

Cited by 121 publications

References 53 publications

Angptl4 links α-cell proliferation following glucagon receptor inhibition with adipose tissue triglyceride metabolism

Angptl4 links α-cell proliferation following glucagon receptor inhibition with adipose tissue triglyceride metabolism

Different Training-Induced Skeletal Muscle Adaptations in COPD Patients with and without Alpha-1 Antitrypsin Deficiency

The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux

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