Featured Articles

Volume 9 | March 2018

Respiromics - Linking mitochondrial bioenergetics to molecular signaturesIn response to physiological and environmental stress, mitochondria adapt to match increased ATP demand and maintain metabolic homeostasis. Intrinsic flexibility and allosteric control are partially supported by adjustments of protein concentrations. However, in particular chronic impairments of energy balance, the limits of these adjustments may be reached, establishing pathologies of the metabolic syndrome. Walheim et al. combine quantitative mitochondrial respirometry and proteomics to understand how molecular changes translate to changes in mitochondrial energy transduction during diet-induced obesity (DIO) in the liver. The integrative analysis highlights the mitochondrial pyruvate carrier as a prime element controlling respiration in the liver.

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Roux en Y gastric bypass hypoglycemia resolves with gastric feeding or reversalRoux-en-Y gastric bypass (RYGB) surgery is the most commonly performed bariatric procedure worldwide and has dramatic effects on weight loss and diabetes remission. Postprandial hypoglycemia is recognized as a late complication of RYGB. Davis and colleagues show that the pathophysiology of this syndrome is not due to inherent changes in pancreatic β-cell mass or function but to reversible alterations caused by RYGB anatomy. RYGB reversal is an effective treatment option in select patients with severe hypoglycemia.

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PGC-1α1 stabilizers induce Ucp1 expression and uncoupled mitochondrial respirationPeroxisome proliferator-activated receptor-γ coactivator-1α1 (PGC-1α1) is a strong regulator of mitochondrial biogenesis and oxidative metabolism. In adipocytes, PGC-1α1 has been shown to coordinate the expression of thermogenic genes, of which uncoupling protein 1 (Ucp1) has central importance. Pettersson-Klein, Izadi and colleagues report the development of a cell-based high-throughput screening system that allows to identify agents that activate PGC-1α1 by increasing protein stability. Using this system, the authors were able to identify several small molecule PGC-1α1 activators that are biologically active in brown adipocytes. Treatment of adipocytes with select compounds lead to PGC-1α1 protein accumulation and increased Ucp1 expression and mitochondrial respiration rates.

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ACSL4 plays a role in phospholipid remodeling and adipocyte dysfunction The long-chain acyl-CoA synthetase (ACSL) family of enzymes catalyze the addition of a coenzyme-A (CoA) group to a fatty acid to form fatty acyl-CoAs, effectively “trapping” FAs within cells. Killion et al. studied the role of ACSL4 in regulating obesity-associated adipocyte dysfunction. In the context of diet-induced obesity, adipocyte ACSL4 regulates adiposity, obesity-associated inflammation and metabolic complications, whole-body energy expenditure, and isolated adipocyte oxygen consumption rate.

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Genome-wide analysis of PDX1 target genes in human pancreatic progenitors PDX1 is a transcription factor expressed in the developing pancreas. Heterozygous mutations in the PDX1 gene cause a strong form of monogenic diabetes. Unravelling PDX target genes may help to understand its contributions to different forms of diabetes. Wang, Sterr, et al. provide a PDX1 regulated human pancreas developmental program that can be used to investigate the effects of PDX1 mutations. They find more than 430 type 2 diabetes (T2DM)-associated SNPs in active regulatory regions and 32% of T2DM genes to be bound by PDX1 in XM001 pancreatic progenitors, demonstrating that PDX1 occupancy is an efficient way to identify important pancreatic developmental and disease genes.

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Circular RNAs as novel regulators of β-cell functions Recent work revealed the presence of thousands of abundant, endogenous circular RNAs (circRNAs) in mammalian cells. Despite their abundance, little is known about the functional role of circRNAs. Stoll and colleagues identify circRNAs expressed in pancreatic islets and elucidate their possible role in the control of β-cell function. The authors find that circHIPK3 and ciRS-7 are highly abundant in pancreatic islets and display reduced expression in diabetes animal models. Silencing these circular transcripts resulted in impaired β-cell function, pointing to a contribution of altered circHIPK3 and ciRS-7 expression in the development of diabetes mellitus.

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TALK-1 reduces delta-cell calcium levels limiting somatostatin secretionSomatostatin is a potent inhibitory peptide, which regulates many physiological processes, such as hormone secretion, neurotransmission, gastric function, and cell proliferation. Although the necessity of proper islet somatostatin secretion for glucose homeostasis is increasingly appreciated, the molecular mechanisms underlying δ-cell function remain poorly understood. Vierra and colleagues investigated whether TALK-1 potassium channels modulate δ-cell Ca2++ handling and somatostatin secretion. The authors found that TALK-1 forms functional channels in mouse and human δ-cells, where it limits Ca2++-induced Ca2++ release and somatostatin secretion.

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Liver-specific rescuing of CEACAM1 reverses endothelial and cardiovascular abnormalities The carcinoembryonic antigen-related cell adhesion molecule-1, CEACAM1, regulates insulin action by promoting receptor-mediated insulin uptake and degradation in the hepatocyte, the main mechanism of insulin clearance. Consistently, Cc1-/- mice with global deletion of Ceacam1 exhibit hyperinsulinemia caused by impaired insulin clearance, followed by insulin resistance. They also develop endothelial and vascular disturbances. Russo, Muturi et al. show that liver-specific rescue of CEACAM1 reverses not only metabolic, but also endothelial and cardiovascular abnormalities, underscoring the critical role of hepatic insulin clearance.

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Ghrelin mediates exercise endurance and the feeding response post-exercise Ghrelin is a stomach-derived hormone that stimulates growth hormone (GH) secretion and affects various processes related to eating, body weight, and blood glucose regulation. Recent studies suggest that the biological importance of endogenous ghrelin is accentuated during exposure to more metabolically constrained and stressful environments. Mani, Castorena, et al. aimed to study the biological significance of the ghrelin system in mice subjected to exercise as a metabolic challenge. Their results suggest that the endogenous ghrelin system is essential for exercise endurance and for the usual food intake response to exercise.

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Reversal of metabolic disorders by activation of bile acid receptors It has been demonstrated that activation of farnesoid X receptor (FXR) improves lipid and glucose homeostasis and inhibits the development of non-alcoholic fatty liver disease (NAFLD) and atherosclerosis. Activation of the bile acid receptor TGR5 improves glucose and energy homeostasis and inhibits atherogenesis. Development of dual agonists for both FXR and TGR5 appears to be an attractive strategy for treatment of common metabolic disorders. Jadhav, Xu, Xu, et al. tested INT-767, a semisynthetic, potent, and specific agonist for both FXR and TGR5. Their data indicate that INT-767 reverses obesity, hypercholesterolemia, NAFLD, and atherosclerosis by activation of FXR and/or TGR5.

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IGF receptor signaling regulates working memory, mitochondrial metabolism, and amyloid-β uptake in astrocytes Insulin-like growth factor-1 (IGF-1) is a potent trophic factor, the levels of which substantially decline with age. In this study, Logan et al. investigated the role of IGF-1 signaling in astrocytic function. They show that spatial learning deficits in aged mice are associated with decreased IGFR expression in the hippocampus and increased gliosis. More importantly, mice with astrocyte-specific knockout of IGFR show impairments in hippocampal-dependent working memory. IGFR deficient astrocytes also displayed altered mitochondrial structure and function and increased mitochondrial ROS production. Age-related astrocytic dysfunction caused by diminished IGF-1 signaling may contribute to the pathogenesis of Alzheimer’s disease and other age-associated cognitive pathologies.

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TRPC proteins contribute to development of diabetic retinopathyDiabetic retinopathy is a prevalent complication that is expected to increase in magnitude given the global epidemic of type 2 diabetes. In this study, Sachdeva, Schlotterer, Schumacher, Matka, and colleagues investigated the causal contribution of four TRPC proteins, TRPC1, TRPC4, TRPC5, and TRPC6 to diabetic retinopathy by comparing Trpc1/4/5/6-/- mice to wild-type controls in the Streptozotocin-induced model of diabetes. They show that TRPC proteins causally contribute to the development of retinopathy in diabetes.

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Vildagliptin for prevention of postpartum diabetesWomen with gestational diabetes (GDM) are at increased risk of developing diabetes in the postpartum period. Hummel et al. asked whether it is possible to reduce the risk of postpartum diabetes in women with prior GDM through pharmacotherapy. They tested the dipeptidyl peptidase-4 inhibitor vildagliptin in an investigator-initiated phase II study with a 2-year treatment period and a one-year follow-up. Administration of vildagliptin did not achieve a significant reduction in the risk of postpartum diabetes compared with placebo in women with prior insulin-requiring GDM at the time of the interim analysis.

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miR-219 regulates differences in response to diet induced weight cycling Weight cycling (WC), the repeated loss and regain of weight, often results in an overall gain rather than loss of weight in the long term. WC has been implicated as an increased risk for eating disorders and metabolic syndrome. Schroeder, Drori, and colleagues were interested in the mechanism underlying the different responses to WC among individuals with a similar genetic and environmental background. They examined individual differences in the metabolic profile of mice subjected to repeated metabolic challenge in parallel to the hypothalamic miRNA footprint. Results suggest a role for miR-219 in the mediation of the metabolic phenotype resulting from repeated weight cycling.

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Exercise increases circulating GDF15 in humans Growth differentiation factor 15 (GDF15) has emerged as a potential anti-obesity agent. It circulates as a 25-kDa homodimer and is a member of the transforming growth factor-β (TGF-β) super family. Kleinert and colleagues identify exercise as a disease-unrelated, physiological stimulus that increases endogenous circulating GDF15 levels in humans. This exercise effect appears to occur without direct contribution from skeletal muscle.

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Cardiac natriuretic peptides promote adipose ‘browning’ Atrial natriuretic peptide and B-type natriuretic peptide are endocrine hormones that are released from the heart in response to increases in cardiac wall stress and other local factors. Liu et al. show that natriuretic peptides activate mammalian target of rapamycin complex 1 (mTORC1), promoting the browning of adipose tissue and leading to increased energy expenditure.

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Distinct adipocyte progenitor cells are associated with regional phenotypes of perivascular aortic fat Perivascular adipose tissue (PVAT) is a newly recognized adipose depot with highly active endocrine and paracrine functions. PVAT surrounding the murine thoracic aorta (tPVAT) exhibits phenotypic features of brown adipose tissue, and PVAT surrounding the abdominal aorta (aPVAT) is more similar to white adipose tissue. It was unclear whether these differences are the result of extrinsic anatomical factors or intrinsic cell autonomic properties. Now, Tran, Fitzgibbons and colleagues demonstrate that preadipocytes residing in tPVAT and aPVAT have cell-autonomous characteristics that dictate phenotypic development.

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Desacetyl-α-MSH and α-MSH are required to regulate energy balanceThe melanocortin system plays a significant role in the regulation of energy balance. However, little is known about which specific endogenous pro-opiomelanocortin (POMC)-derived peptides are responsible for regulation of appetite, metabolism, and body weight. Among these peptides are α-melanocyte stimulating hormone (α-MSH) and its precursor desacetyl-α-MSH. Mountjoy et al. determined the direct contribution of desacetyl-α-MSH and α-MSH in regulating energy balance. They show that desacetyl-α-MSH is indeed biologically active in vivo and, like α-MSH, it can reduce mouse body weight and fat mass.

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The 60 Second Metabolist
In this section authors briefly report on their work recently published in Molecular Metabolism.

Watch the most recent interview by clicking the video still. The link "referring article" directs you to this author's publication.



Abdelfattah El Ouaamari
Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, USA
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