Metabolism
Abstract
The hepatic glucose fasting response is gaining traction as a therapeutic pathway to enhance hepatic and whole-host metabolism. However, the mechanisms underlying these metabolic effects remain unclear. Here, we demonstrate the epidermal-type lipoxygenase, eLOX3 (encoded by its gene, Aloxe3), is a potentially novel effector of the therapeutic fasting response. We show that Aloxe3 is activated during fasting, glucose withdrawal, or trehalose/trehalose analogue treatment. Hepatocyte-specific Aloxe3 expression reduced weight gain and hepatic steatosis in diet-induced and genetically obese (db/db) mouse models. Aloxe3 expression, moreover, enhanced basal thermogenesis and abrogated insulin resistance in db/db diabetic mice. Targeted metabolomics demonstrated accumulation of the PPARγ ligand 12-KETE in hepatocytes overexpressing Aloxe3. Strikingly, PPARγ inhibition reversed hepatic Aloxe3–mediated insulin sensitization, suppression of hepatocellular ATP production and oxygen consumption, and gene induction of PPARγ coactivator-1α (PGC1α) expression. Moreover, hepatocyte-specific PPARγ deletion reversed the therapeutic effect of hepatic Aloxe3 expression on diet-induced insulin intolerance. Aloxe3 is, therefore, a potentially novel effector of the hepatocellular fasting response that leverages both PPARγ-mediated and pleiotropic effects to augment hepatic and whole-host metabolism, and it is, thus, a promising target to ameliorate metabolic disease.
Authors
Cassandra B. Higgins, Yiming Zhang, Allyson L. Mayer, Hideji Fujiwara, Alicyn I. Stothard, Mark J. Graham, Benjamin M. Swarts, Brian J. DeBosch
Abstract
Chronic kidney disease (CKD) leads to decreased sensitivity to the metabolic effects of insulin, contributing to protein energy wasting and muscle atrophy. Targeted metabolomics profiling during hyperinsulinemic-euglycemic insulin clamp testing may help identify aberrant metabolic pathways contributing to insulin resistance in CKD. Using targeted metabolomics profiling, we examined the plasma metabolome in 95 adults without diabetes in the fasted state (58 with CKD, 37 with normal glomerular filtration rate [GFR]) who underwent hyperinsulinemic-euglycemic clamp. We assessed heterogeneity in fasting metabolites and the response to insulin to identify potential metabolic pathways linking CKD with insulin resistance. Baseline differences and effect modification by CKD status on changes with insulin clamp testing were adjusted for confounders. Mean GFR among participants with CKD was 37.3 compared with 89.3 ml/min per 1.73 m2 among controls. Fasted-state differences between CKD and controls included abnormalities in tryptophan metabolism, ubiquinone biosynthesis, and the TCA cycle. Insulin infusion markedly decreased metabolite levels, predominantly amino acids and their metabolites. CKD was associated with attenuated insulin-induced changes in nicotinamide, arachidonic acid, and glutamine/glutamate metabolic pathways. Metabolomics profiling suggests disruption in amino acid metabolism and mitochondrial function as putative manifestations or mechanisms of the impaired anabolic effects of insulin in CKD.
Authors
Baback Roshanravan, Leila R. Zelnick, Daniel Djucovic, Haiwei Gu, Jessica A. Alvarez, Thomas R. Ziegler, Jorge L. Gamboa, Kristina Utzschneider, Bryan Kestenbaum, Jonathan Himmelfarb, Steven E. Kahn, Daniel Raftery, Ian H. de Boer
Abstract
The human adaptive starvation response allows for survival during long-term caloric deprivation. Whether the physiology of starvation is adaptive or maladaptive is context dependent: activation of pathways by caloric restriction may promote longevity, yet in the context of caloric excess, the same pathways may contribute to obesity. Here, we performed plasma metabolite profiling of longitudinally collected samples during a 10-day, 0-calorie fast in humans. We identify classical milestones in adaptive starvation, including the early consumption of gluconeogenic amino acids and the subsequent surge in plasma nonesterified fatty acids that marks the shift from carbohydrate to lipid metabolism, and demonstrate findings, including (a) the preferential release of unsaturated fatty acids and an associated shift in plasma lipid species with high degrees of unsaturation and (b) evidence that acute, starvation-mediated hypoleptinemia may be a driver of the transition from glucose to lipid metabolism in humans.
Authors
Matthew L. Steinhauser, Benjamin A. Olenchock, John O’Keefe, Mingyue Lun, Kerry A. Pierce, Hang Lee, Lorena Pantano, Anne Klibanski, Gerald I. Shulman, Clary B. Clish, Pouneh K. Fazeli
Abstract
Alterations in the synthesis and bioavailability of NO are central to the pathogenesis of cardiovascular and metabolic disorders. Although endothelial NO synthase–derived (eNOS-derived) NO affects mitochondrial long-chain fatty acid β-oxidation, the pathophysiological significance of this regulation remains unclear. Accordingly, we determined the contributions of eNOS/NO signaling in the adaptive metabolic responses to fasting and in age-induced metabolic dysfunction. Four-month-old eNOS–/– mice are glucose intolerant and exhibit serum dyslipidemia and decreased capacity to oxidize fatty acids. However, during fasting, eNOS–/– mice redirect acetyl-CoA to ketogenesis to elevate circulating levels of β-hydroxybutyrate similar to wild-type mice. Treatment of 4-month-old eNOS–/– mice with nitrite for 10 days corrected the hypertension and serum hyperlipidemia and normalized the rate of fatty acid oxidation. Fourteen-month-old eNOS–/– mice exhibited metabolic derangements, resulting in reduced utilization of fat to generate energy, lower resting metabolic activity, and diminished physical activity. Seven-month administration of nitrite to eNOS–/– mice reversed the age-dependent metabolic derangements and restored physical activity. While the eNOS/NO signaling is not essential for the metabolic adaptation to fasting, it is critical for regulating systemic metabolic homeostasis in aging. The development of age-dependent metabolic disorder is prevented by low-dose replenishment of bioactive NO.
Authors
Margarita Tenopoulou, Paschalis-Thomas Doulias, Kent Nakamoto, Kiara Berrios, Gabriella Zura, Chenxi Li, Michael Faust, Veronika Yakovishina, Perry Evans, Lu Tan, Michael J. Bennett, Nathaniel W. Snyder, William J. Quinn III, Joseph A. Baur, Dmitriy N. Atochin, Paul L. Huang, Harry Ischiropoulos
Abstract
Little is known about the biological function of histone deacetylase 11 (HDAC11), which is the lone class IV HDAC. Here, we demonstrate that deletion of HDAC11 in mice stimulates brown adipose tissue (BAT) formation and beiging of white adipose tissue (WAT). Consequently, HDAC11-deficient mice exhibit enhanced thermogenic potential and, in response to high-fat feeding, attenuated obesity, improved insulin sensitivity, and reduced hepatic steatosis. Ex vivo and cell-based assays revealed that HDAC11 catalytic activity suppresses the BAT transcriptional program, in both the basal state and in response to β-adrenergic receptor signaling, through a mechanism that is dependent on physical association with BRD2, a bromodomain and extraterminal (BET) acetyl-histone-binding protein. These findings define an epigenetic pathway for the regulation of energy homeostasis and suggest the potential for HDAC11-selective inhibitors for the treatment of obesity and diabetes.
Authors
Rushita A. Bagchi, Bradley S. Ferguson, Matthew S. Stratton, Tianjing Hu, Maria A. Cavasin, Lei Sun, Ying-Hsi Lin, Dianxin Liu, Pilar Londono, Kunhua Song, Maria F. Pino, Lauren M. Sparks, Steven R. Smith, Philipp E. Scherer, Sheila Collins, Edward Seto, Timothy A. McKinsey
Abstract
BACKGROUND. The duration and patterns of β cell dysfunction during type 1 diabetes (T1D) development have not been fully defined. METHODS. Metabolic measures derived from oral glucose tolerance tests (OGTTs) were compared between autoantibody-positive (aAb+) individuals followed in the TrialNet Pathway to Prevention study who developed diabetes after 5 or more years or less than 5 years of longitudinal follow-up (Progressors≥5, n = 75; Progressors<5, n = 474) and 144 aAb-negative (aAb–) relatives. RESULTS. Mean age at study entry was 15.0 ± 12.6 years for Progressors≥5; 12.0 ± 9.1 for Progressors<5; and 16.3 ± 10.4 for aAb– relatives. At baseline, Progressors≥5 already exhibited significantly lower fasting C-peptide (P < 0.01), C-peptide AUC (P < 0.001), and early C-peptide responses (30- to 0-minute C-peptide; P < 0.001) compared with aAb– relatives, while 2-hour glucose (P = 0.03), glucose AUC (<0.001), and Index60 (<0.001) were all higher. Despite significant baseline impairment, metabolic measures in Progressors≥5 were relatively stable until 2 years prior to T1D diagnosis, when there was accelerated C-peptide decline and rising glycemia from 2 years until diabetes diagnosis. Remarkably, patterns of progression within 3 years of diagnosis were nearly identical between Progressors≥5 and Progressors<5. CONCLUSION. These data provide insight into the chronicity of β cell dysfunction in T1D and indicate that β cell dysfunction may precede diabetes diagnosis by more than 5 years in a subset of aAb+ individuals. Even among individuals with varying lengths of aAb positivity, our findings indicate that patterns of metabolic decline are uniform within the last 3 years of progression to T1D. TRIAL REGISTRATION. Clinicaltrials.gov NCT00097292. FUNDING. The Type 1 Diabetes TrialNet Study Group is a clinical trials network currently funded by the NIH through the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Juvenile Diabetes Research Foundation.
Authors
Carmella Evans-Molina, Emily K. Sims, Linda A. DiMeglio, Heba M. Ismail, Andrea K. Steck, Jerry P. Palmer, Jeffrey P. Krischer, Susan Geyer, Ping Xu, Jay M. Sosenko, the Type 1 Diabetes TrialNet Study Group
Abstract
BACKGROUND. Exercise has profound pleiotropic health benefits, yet the underlying mechanisms remain incompletely understood. Endocrine FGF21, bile acids (BAs), and BA-induced FGF19 have emerged as metabolic signaling molecules. Here, we investigated if dissimilar modes of exercise, resistance exercise (RE) and endurance exercise (EE), regulate plasma BAs, FGF19, and FGF21 in humans. METHODS. Ten healthy, moderately trained males were enrolled in a randomized crossover study of 1 hour of bicycling at 70% of VO2peak (EE) and 1 hour of high-volume RE. Hormones and metabolites were measured in venous blood and sampled before and after exercise and at 15, 30, 60, 90, 120, and 180 minutes after exercise. RESULTS. We observed exercise mode–specific changes in plasma concentrations of FGF19 and FGF21. Whereas FGF19 decreased following RE (P < 0.001), FGF21 increased in response to EE (P < 0.001). Total plasma BAs decreased exclusively following RE (P < 0.05), but the composition of BAs changed in response to both types of exercise. Notably, circulating levels of the potent TGR5 receptor agonist, lithocholic acid, increased with both types of exercise (P < 0.001). CONCLUSION. This study reveals divergent effects of EE and RE on circulating concentrations of the BA species, FGF19, and FGF21. We identify temporal relationships between decreased BA and FGF19 following RE and a sharp disparity in FGF21 concentrations, with EE eliciting a clear increase parallel to that of glucagon. FUNDING. The Novo Nordisk Foundation (NNF17OC0026114) and the Lundbeck Foundation (R238-2016-2859).
Authors
Thomas Morville, Ronni E. Sahl, Samuel A.J. Trammell, Jens S. Svenningsen, Matthew P. Gillum, Jørn W. Helge, Christoffer Clemmensen
Abstract
BACKGROUND. The induction of beige adipocytes in s.c. white adipose tissue (WAT) depots of humans is postulated to improve glucose and lipid metabolism in obesity. The ability of obese, insulin-resistant humans to induce beige adipose tissue is unknown. METHODS. We exposed lean and obese research participants to cold (30-minute ice pack application each day for 10 days of the upper thigh) or treated them with the β3 agonist mirabegron. We determined beige adipose marker expression by IHC and quantitative PCR, and we analyzed mitochondrial bioenergetics and UCP activity with an Oxytherm system. RESULTS. Cold significantly induced UCP1 and TMEM26 protein in both lean and obese subjects, and this response was not associated with age. Interestingly, these proteins increased to the same extent in s.c. WAT of the noniced contralateral leg, indicating a crossover effect. We further analyzed the bioenergetics of purified mitochondria from the abdominal s.c. WAT of cold-treated subjects and determined that repeat ice application significantly increased uncoupled respiration, consistent with the UCP1 protein induction and subsequent activation. Cold also increased State 3 and maximal respiration, and this effect on mitochondrial bioenergetics was stronger in summer than winter. Chronic treatment (10 weeks; 50 mg/day) with the β3 receptor agonist mirabegron induces UCP1, TMEM26, CIDEA, and phosphorylation of HSL on serine660 in obese subjects. CONCLUSION. Cold or β3 agonists cause the induction of beige adipose tissue in human s.c. WAT; this phenomenon may be exploited to increase beige adipose in older, insulin-resistant, obese individuals. TRIAL REGISTRATION. Clinicaltrials.gov NCT02596776, NCT02919176. FUNDING. NIH (DK107646, DK112282, P20GM103527, and by CTSA grant UL1TR001998).
Authors
Brian S. Finlin, Hasiyet Memetimin, Amy L. Confides, Ildiko Kasza, Beibei Zhu, Hemendra J. Vekaria, Brianna Harfmann, Kelly A. Jones, Zachary R. Johnson, Philip M. Westgate, Caroline M. Alexander, Patrick G. Sullivan, Esther E. Dupont-Versteegden, Philip A. Kern
Abstract
Aldosterone synthase inhibitors (ASIs) should alleviate obesity-related cardiovascular and renal problems resulting partly from aldosterone excess, but their clinical use may have limitations. To improve knowledge for the use of ASIs, we investigated physiology in aldosterone synthase–knockout (ASKO) mice. On regular chow diet (CD), ASKO mice ate more and weighed less than WT mice, largely because they hyperventilated to eliminate acid as CO2. Replacing CD with high-fat diet (HFD) lessened the respiratory burden in ASKO mice, as did 12- to 15-hour fasting. The latter eliminated the genotype differences in respiratory workload and energy expenditure (EE). Thus, aldosterone deficiency burdened the organism more when the animals ate carbohydrate-rich chow than when they ate a HFD. Chronic HFD exposure further promoted hyperinsulinemia in ASKO mice that contributed to visceral fat accumulation accompanied by reduced lipolysis, thermogenic reprogramming, and the absence of weight-gain-related EE increases. Intracerebroventricular aldosterone supplementation in ASKO mice attenuated the HFD-induced hyperinsulinemia, but did not affect EE, suggesting that the presence of aldosterone increased the body’s energetic efficiency, thus counteracting the EE-increasing effect of low insulin. ASIs may therefore cause acid-overload-induced respiratory burden and promote obesity. Their use in patients with preexisting renal and cardiopulmonary diseases might be contraindicated.
Authors
Wan-Hui Liao, Claudia Suendermann, Andrea Eva Steuer, Gustavo Pacheco Lopez, Alex Odermatt, Nourdine Faresse, Maciej Henneberg, Wolfgang Langhans
Abstract
The neuropathological effects of phenylketonuria (PKU) stem from the inability of the body to metabolize excess phenylalanine (Phe), resulting in accumulation of Phe in the blood and brain. Since the kidney normally reabsorbs circulating amino acids with high efficiency, we hypothesized that preventing the renal uptake of Phe might provide a disposal pathway that could lower systemic Phe levels. SLC6A19 is a neutral amino acid transporter responsible for absorption of the majority of free Phe in the small intestine and reuptake of Phe by renal proximal tubule cells. Transgenic KO mice lacking SLC6A19 have elevated levels of Phe and other amino acids in their urine but are otherwise healthy. Here, we crossed the Pahenu2 mouse model of PKU with the Slc6a19-KO mouse. These mutant/KO mice exhibited abundant excretion of Phe in the urine and an approximately 70% decrease in plasma Phe levels. Importantly, brain Phe levels were decreased by 50%, and the levels of key neurotransmitters were increased in the mutant/KO mice. In addition, a deficit in spatial working memory and markers of neuropathology were corrected. Finally, treatment of Pahenu2 mice with Slc6a19 antisense oligonucleotides lowered Phe levels. The results suggest that inhibition of SLC6A19 may represent a novel approach for the treatment of PKU and related aminoacidopathies.
Authors
Adam M. Belanger, Malgorzata Przybylska, Estelle Gefteas, Matthew Furgerson, Sarah Geller, Alla Kloss, Seng H. Cheng, Yunxiang Zhu, Nelson S. Yew
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