Metabolism
Abstract
Paracrine interactions between pancreatic islet cells have been proposed as a mechanism to regulate hormone secretion and glucose homeostasis. Here, we demonstrate the importance of proglucagon-derived peptides (PGDPs) for α- to β-cell communication and control of insulin secretion. Signaling through this system occurs through both the glucagon-like peptide receptor (Glp1r) and glucagon receptor (Gcgr). Loss of PGDPs, or blockade of their receptors, decreases insulin secretion in response to both metabolic and non-metabolic stimulation of mouse and human islets. This effect is due to reduced β-cell cAMP and affects the quantity but not dynamics of insulin release, indicating that PGDPs dictate the magnitude of insulin output in an isolated islet. In healthy mice, additional factors that stimulate cAMP can compensate for loss of PGDP signaling; however, input from α-cells is essential to maintain glucose tolerance during the metabolic stress induced by high-fat feeding. These findings demonstrate an essential role for α-cell regulation of β-cells, raising the possibility that abnormal paracrine signaling contributes to impaired insulin secretion in diabetes. Moreover, these findings support reconsideration of the role for α-cells in postprandial glucose control.
Authors
Megan E. Capozzi, Berit Svendsen, Sara E. Encisco, Sophie L. Lewandowski, Mackenzie D. Martin, Haopeng Lin, Justin L. Jaffe, Reilly W. Coch, Jonathan M. Haldeman, Patrick E. MacDonald, Matthew J. Merrins, David A. D'Alessio, Jonathan E. Campbell
Abstract
Abnormal activation of neddylation modification and dysregulated energy metabolism are frequently seen in many types of cancer cells. Whether and how neddylation modification affects cellular metabolism remains largely unknown. Here we showed that MLN4924, a small molecule inhibitor of neddylation modification, induces mitochondrial fission-to-fusion conversion in breast cancer cells via inhibiting ubiquitylation and degradation of fusion-promoting protein mitofusin (MFN1) by SCFβ-TrCP E3 ligase and blocking the mitochondrial translocation of fusion-inhibiting protein DRP1. Importantly, MLN4924-induced mitochondrial fusion is independent of cell cycle progression, but confers cellular survival. The Mass-Spectrometry-based metabolic profiling and mitochondrial functional assays reveal that MLN4924 inhibits TCA cycle, but promotes mitochondrial OXPHOS. MLN4924 also increases glycolysis by activating PKM2 via promoting its tetramerization. Biologically, MLN4924 coupled with OXPHOS inhibitor metformin, or glycolysis inhibitor shikonin, significantly inhibits cancer cell growth both in vitro and in vivo. Together, our study links neddylation modification and energy metabolism, and provides sound strategies for effective combinational cancer therapies.
Authors
Qiyin Zhou, Hua Li, Yuanyuan Li, Mingjia Tan, Shaohua Fan, Cong Cao, Feilong Meng, Ling Zhu, Lili Zhao, Min-Xin Guan, Hongchuan Jin, Yi Sun
Abstract
Evidence has emerged that the failing heart increases utilization of ketone bodies. We sought to determine whether this fuel shift is adaptive. Mice rendered incapable of oxidizing the ketone body 3-hydroxybutyrate (3OHB) in heart exhibited worsened heart failure in response to fasting or a pressure overload/ischemic insult compared to wild-type controls. Increased delivery of 3OHB ameliorated pathologic cardiac remodeling and dysfunction in mice and in a canine pacing model of progressive heart failure. 3OHB was shown to enhance bioenergetic thermodynamics of isolated mitochondria in the context of limiting levels of fatty acids. These results indicate that the heart utilizes 3OHB as a metabolic stress defense and suggest that strategies aimed at increasing ketone delivery to the heart could prove useful in the treatment of heart failure.
Authors
Julie L. Horton, Michael T. Davidson, Clara Kurishima, Rick B. Vega, Jeffery C. Powers, Timothy R. Matsuura, Christopher Petucci, E. Douglas Lewandowski, Peter A. Crawford, Deborah M. Muoio, Fabio A. Recchia, Daniel P. Kelly
Abstract
Acute lung injury (ALI) is characterized by exuberant proinflammatory responses and mitochondrial dysfunction. However, the link between mitochondrial dysfunction and inflammation in ALI is not well understood. In this report, we demonstrate a critical role for the mitochondrial NAD+-dependent deacetylase, sirtuin-3 (SIRT3), in regulating macrophage mitochondrial bioenergetics, ROS formation, and proinflammatory responses. We found that SIRT3 expression was significantly diminished in lungs of mice subjected to LPS-induced ALI. SIRT3-deficient mice (SIRT3–/–) develop more severe ALI compared with wild-type controls (SIRT3+/+). Macrophages obtained from SIRT3–/– mice show significant alterations in mitochondrial bioenergetic and redox homeostasis, in association with a proinflammatory phenotype characterized by NLRP3 inflammasome activation. The SIRT3 activator viniferin restored macrophage bioenergetic function in LPS-treated macrophages. Viniferin also reduced NLRP3 activation and the production of proinflammatory cytokines, effects that were absent in SIRT3–/– macrophages. In-vivo administration of viniferin reduced production of inflammatory mediators TNF-α, MIP-2, IL-6, IL-1β, and HMGB1, and diminished neutrophil influx and severity of endotoxin-mediated ALI; this protective effect of vinferin was abolished in SIRT3–/– mice. Taken together, our results show that the induction/activation of SIRT3 may serve as a new therapeutic strategy in ALI by modulating cellular bioenergetics, controlling inflammatory responses, and reducing the severity of lung injury.
Authors
Deepali Kurundkar, Ashish R. Kurundkar, Nathaniel B. Bone, Eugene J. Becker Jr., Wanqu Liu, Balu Chacko, Victor Darley-Usmar, Jaroslaw W. Zmijewski, Victor J. Thannickal
Abstract
BACKGROUND. Weight gain and metabolic changes during treatment with antidepressant drugs have emerged as an important concern, particularly in long-term treatment. It is still a matter of ongoing debate whether weight gain and metabolic perturbations with antidepressant use are the consequence of increased appetite and weight gain, respectively, or represents direct pharmacological effects of the drug on metabolism. METHODS. We therefore conducted a proof-of-concept, open-label clinical trial, hypothesizing that in exceptionally healthy men no change of metabolic parameters would occur under mirtazapine, when environmental factors such as nutrition, sleep, and physical exercise were controlled and kept constant. Over a 3-week preparation phase, 10 healthy, young men were attuned to a standardized diet adjusted to their individual caloric need, to a regular sleep/wake cycle and moderate exercise. Continuing this protocol, we administered 30 mg mirtazapine daily for 7 days. RESULTS. While no significant weight gain or changes in resting energy expenditure were observed under these conditions, hunger and appetite for sweets increased with mirtazapine, accompanied by a shift in energy substrate partitioning towards carbohydrate substrate preference as assessed by indirect calorimetry. Furthermore, with mirtazapine, insulin and C-peptide release increased in response to a standardized meal. CONCLUSION. Our findings provide important insights into weight-independent metabolic changes associated with mirtazapine and allow a better understanding of the long-term metabolic effects observed in patients treated with antidepressant drugs. TRIAL REGISTRATION. ClinicalTrials.gov NCT00878540. FUNDING. Nothing to declare.
Authors
Johannes M. Hennings, Sarah Heel, Katharina Lechner, Manfred Uhr, Tatjana Dose, Ludwig Schaaf, Florian Holsboer, Susanne Lucae, Stephany Fulda, Stefan Kloiber
Abstract
Obese individuals are often at risk for nonalcoholic fatty liver disease (NAFLD), insulin resistance, type 2 diabetes (T2D), and cardiovascular diseases such as angina, thereby requiring combination therapies for their comorbidities. Ranolazine is a second-line antianginal agent that also improves glycemia, and our aim was to determine whether ranolazine modifies the progression of obesity-induced NAFLD. Twelve-week-old C57BL/6J male mice were fed a low-fat or high-fat diet for 10 weeks and then treated for 30 days with either vehicle control or ranolazine (50 mg/kg via daily s.c. injection). Glycemia was monitored via glucose/pyruvate/insulin tolerance testing, whereas in vivo metabolism was assessed via indirect calorimetry. Hepatic triacylglycerol content was quantified via the Bligh and Dyer method. Consistent with previous reports, ranolazine treatment reversed obesity-induced glucose intolerance, which was associated with reduced body weight and hepatic steatosis, as well as increased hepatic pyruvate dehydrogenase (PDH) activity. Ranolazine’s actions on hepatic PDH activity may be directly mediated, as ranolazine treatment reduced PDH phosphorylation (indicative of increased PDH activity) in HepG2 cells. Therefore, in addition to mitigating angina, ranolazine also reverses NAFLD, which may contribute to its documented glucose-lowering actions, situating ranolazine as an ideal antianginal therapy for obese patients comorbid for NAFLD and T2D.
Authors
Rami Al Batran, Keshav Gopal, Hanin Aburasayn, Amina Eshreif, Malak Almutairi, Amanda A. Greenwell, Scott A. Campbell, Bruno Saleme, Emily A. Court, Farah Eaton, Peter E. Light, Gopinath Sutendra, John R. Ussher
Abstract
White adipose tissue (WAT) can dynamically expand and remodel through adipocyte hypertrophy and hyperplasia. The relative contribution of these 2 mechanisms to WAT expansion is a critical determinant of WAT function and dysfunction in obesity. However, little is known about the signaling systems that determine the mechanisms of WAT expansion. Here, we show that the GPCR LPA4 selectively activates Gα12/13 proteins in adipocytes and limits continuous remodeling and healthy expansion of WAT. LPA4-KO mice showed enhanced expression of mitochondrial and adipogenesis genes and reduced levels of inhibitory phosphorylation of PPARγ in WAT, along with increased production of adiponectin. Furthermore, LPA4-KO mice showed metabolically healthy obese phenotypes in a diet-induced obesity model, with continuous WAT expansion, as well as protection from WAT inflammation, hepatosteatosis, and insulin resistance. These findings unravel a potentially new signaling system that underlies WAT plasticity and expandability, providing a promising therapeutic approach for obesity-related metabolic disorders.
Authors
Keisuke Yanagida, Hidemitsu Igarashi, Daisuke Yasuda, Daiki Kobayashi, Takayo Ohto-Nakanishi, Noriyuki Akahoshi, Atsushi Sekiba, Tsudoi Toyoda, Tomoko Ishijima, Yuji Nakai, Nobuhiro Shojima, Naoto Kubota, Keiko Abe, Takashi Kadowaki, Satoshi Ishii, Takao Shimizu
Abstract
BACKGROUND. Excessive insulin secretion may lead to glucose dysregulation. Our aim was to identify primary (independent of insulin resistance) insulin hypersecretion in subjects with normal glucose tolerance and its role in the progression of dysglycemia. METHODS. In 1,168 adults, insulin secretion rate (ISR) and β cell function were estimated by C-peptide modeling during an oral glucose tolerance test (OGTT) and an i.v. glucose tolerance test. Whole-body insulin sensitivity was measured by a hyperinsulinemic-euglycemic clamp. After regressing ISR on insulin sensitivity, subjects in the upper tertile of the distribution of residuals were defined as primary hypersecretors. This approach was applied to a biethnic cohort of 182 obese adolescents, who received an OGTT, a hyperglycemic, and a euglycemic clamp. RESULTS. Adult hypersecretors showed older age, more familial diabetes, sedentary lifestyle, increased fat mass, and worse lipid profile compared with the rest of the cohort, despite virtually identical BMI and insulin sensitivity. Insulin secretion was increased by 53% due to enhanced (+23%) β cell glucose sensitivity. Despite the resulting hyperinsulinemia, glucose tolerance was worse in hypersecretors among both adults and adolescents, coupled with higher indices of liver insulin resistance and increased availability of gluconeogenic substrates. At the 3-year follow-up, adult hypersecretors had increased incidence of impaired glucose tolerance/type 2 diabetes. CONCLUSION. Primary insulin hypersecretion, independent of insulin resistance, is associated with a worse clinical and metabolic phenotype in adults and adolescents and predicts deterioration of glucose control over time. FUNDING. The relationship between insulin sensitivity and cardiovascular disease (RISC) Study was partly supported by EU grant QLG1-CT-2001-01252.
Authors
Domenico Tricò, Andrea Natali, Silva Arslanian, Andrea Mari, Ele Ferrannini
Abstract
Sialic acids are important components of glycoproteins and glycolipids essential for cellular communication, infection, and metastasis. The importance of sialic acid biosynthesis in human physiology is well illustrated by the severe metabolic disorders in this pathway. However, the biological role of sialic acid catabolism in humans remains unclear. Here, we present evidence that sialic acid catabolism is important for heart and skeletal muscle function and development in humans and zebrafish. In two siblings, presenting with sialuria, exercise intolerance/muscle wasting, and cardiac symptoms in the brother, compound heterozygous mutations [chr1:182775324C>T (c.187C>T; p.Arg63Cys) and chr1:182772897A>G (c.133A>G; p.Asn45Asp)] were found in the N-acetylneuraminate pyruvate lyase gene (NPL). In vitro, NPL activity and sialic acid catabolism were affected, with a cell-type-specific reduction of N-acetyl mannosamine (ManNAc). A knockdown of NPL in zebrafish resulted in severe skeletal myopathy and cardiac edema, mimicking the human phenotype. The phenotype was rescued by expression of wild-type human NPL but not by the p.Arg63Cys or p.Asn45Asp mutants. Importantly, the myopathy phenotype in zebrafish embryos was rescued by treatment with the catabolic products of NPL: N-acetyl glucosamine (GlcNAc) and ManNAc; the latter also rescuing the cardiac phenotype. In conclusion, we provide the first report to our knowledge of a human defect in sialic acid catabolism, which implicates an important role of the sialic acid catabolic pathway in mammalian muscle physiology, and suggests opportunities for monosaccharide replacement therapy in human patients.
Authors
Xiao-Yan Wen, Maja Tarailo-Graovac, Koroboshka Brand-Arzamendi, Anke Willems, Bojana Rakic, Karin Huijben, Afitz Da Silva, Xuefang Pan, Suzan El-Rass, Robin Ng, Katheryn Selby, Anju Mary Philip, Junghwa Yun, X. Cynthia Ye, Colin J. Ross, Anna M. Lehman, Fokje Zijlstra, N. Abu Bakar, Britt Drögemöller, Jacqueline Moreland, Wyeth W. Wasserman, Hilary Vallance, Monique van Scherpenzeel, Farhad Karbassi, Martin Hoskings, Udo Engelke, Arjan de Brouwer, Ron A. Wevers, Alexey V. Pshezhetsky, Clara D.M. van Karnebeek, Dirk J. Lefeber
Abstract
Methylmalonic acidemia (MMA), an organic acidemia characterized by metabolic instability and multiorgan complications, is most frequently caused by mutations in methylmalonyl-CoA mutase (MUT). To define the metabolic adaptations in MMA in acute and chronic settings, we studied a mouse model generated by transgenic expression of Mut in the muscle. Mut–/–;TgINS-MCK-Mut mice accurately replicate the hepatorenal mitochondriopathy and growth failure seen in severely affected patients and were used to characterize the response to fasting. The hepatic transcriptome in MMA mice was characterized by the chronic activation of stress-related pathways and an aberrant fasting response when compared with controls. A key metabolic regulator, Fgf21, emerged as a significantly dysregulated transcript in mice and was subsequently studied in a large patient cohort. The concentration of plasma FGF21 in MMA patients correlated with disease subtype, growth indices, and markers of mitochondrial dysfunction but was not affected by renal disease. Restoration of liver Mut activity, by transgenesis and liver-directed gene therapy in mice or liver transplantation in patients, drastically reduced plasma FGF21 and was associated with improved outcomes. Our studies identify mitocellular hormesis as a hepatic adaptation to metabolic stress in MMA and define FGF21 as a highly predictive disease biomarker.
Authors
Irini Manoli, Justin R. Sysol, Madeline W. Epping, Lina Li, Cindy Wang, Jennifer L. Sloan, Alexandra Pass, Jack Gagné, Yiouli P. Ktena, Lingli Li, Niraj S. Trivedi, Bazoumana Ouattara, Patricia M. Zerfas, Victoria Hoffmann, Mones Abu-Asab, Maria G. Tsokos, David E. Kleiner, Caterina Garone, Kristina Cusmano-Ozog, Gregory M. Enns, Hilary J. Vernon, Hans C. Andersson, Stephanie Grunewald, Abdel G. Elkahloun, Christiane L. Girard, Jurgen Schnermann, Salvatore DiMauro, Eva Andres-Mateos, Luk H. Vandenberghe, Randy J. Chandler, Charles P. Venditti
No posts were found with this tag.
