Metabolism
Abstract
Type 2 diabetes mellitus (T2DM) has become an expanding global public health problem. Although the glucocorticoid receptor (GR) is an important regulator of glucose metabolism, the relationship between circulating glucocorticoids (GCs) and the features of T2DM remains controversial. Here, we show that 17-hydroxyprogesterone (17-OHP), an intermediate steroid in the biosynthetic pathway that converts cholesterol to cortisol, binds to and stimulates the transcriptional activity of GR. Hepatic 17-OHP concentrations are increased in diabetic mice and patients due to aberrantly increased expression of Cyp17A1. Systemic administration of 17-OHP or overexpression of Cyp17A1 in the livers of lean mice promoted the pathogenesis of hyperglycemia and insulin resistance, whereas knockdown of Cyp17A1 abrogated metabolic disorders in obese mice. Therefore, our results identify a Cyp17A1/17-OHP/GR–dependent pathway in the liver that mediates obesity-induced hyperglycemia, suggesting that selectively targeting hepatic Cyp17A1 may provide a therapeutic avenue for treating T2DM.
Authors
Yan Lu, E Wang, Ying Chen, Bing Zhou, Jiejie Zhao, Liping Xiang, Yiling Qian, Jingjing Jiang, Lin Zhao, Xuelian Xiong, Zhiqiang Lu, Duojiao Wu, Bin Liu, Jing Yan, Rong Zhang, Huijie Zhang, Cheng Hu, Xiaoying Li
Abstract
Phosphoglycerate dehydrogenase (PHGDH), the first rate-limiting enzyme of serine synthesis, is frequently overexpressed in human cancer. PHGDH overexpression activates serine synthesis to promote cancer progression. Currently, PHGDH regulation in normal cells and cancer is not well understood. Parkin, an E3 ubiquitin ligase involved in Parkinson’s disease, is a tumor suppressor. Parkin expression is frequently downregulated in many types of cancer, and its tumor-suppressive mechanism is poorly defined. Here, we show that PHGDH is a substrate for Parkin-mediated ubiquitination and degradation. Parkin interacted with PHGDH and ubiquitinated PHGDH at lysine 330, leading to PHGDH degradation to suppress serine synthesis. Parkin deficiency in cancer cells stabilized PHGDH and activated serine synthesis to promote cell proliferation and tumorigenesis, which was largely abolished by targeting PHGDH with RNA interference, CRISPR/Cas9 KO, or small-molecule PHGDH inhibitors. Furthermore, Parkin expression was inversely correlated with PHGDH expression in human breast cancer and lung cancer. Our results revealed PHGDH ubiquitination by Parkin as a crucial mechanism for PHGDH regulation that contributes to the tumor-suppressive function of Parkin and identified Parkin downregulation as a critical mechanism underlying PHGDH overexpression in cancer.
Authors
Juan Liu, Cen Zhang, Hao Wu, Xiao-Xin Sun, Yanchen Li, Shan Huang, Xuetian Yue, Shou-En Lu, Zhiyuan Shen, Xiaoyang Su, Eileen White, Bruce G. Haffty, Wenwei Hu, Zhaohui Feng
Abstract
Nonalcoholic fatty liver disease (NAFLD) is becoming a major health issue as obesity increases around the world. We studied the effect of a circadian locomotor output cycles kaput (CLOCK) mutant (ClkΔ19/Δ19) protein on hepatic lipid metabolism in C57Bl6 Clkwt/wt and apolipoprotein E–deficient (Apoe−/−) mice. Both ClkΔ19/Δ19 and ClkΔ19/Δ19Apoe−/− mice developed a full spectrum of liver diseases (steatosis, steatohepatitis, cirrhosis, and hepatocellular carcinoma) recognized in human NAFLD when challenged with a Western diet, lipopolysaccharide, or CoCl2. We identified induction of cluster of differentiation 36 (CD36) and hypoxia-inducible factor 1α (HIF1α) proteins as contributing factors for NAFLD. Mechanistic studies showed that wild-type CLOCK protein interacted with the E-box enhancer elements in the promoters of the proline hydroxylase domain (PHD) proteins to increase expression. In ClkΔ19/Δ19 mice, PHD levels were low, and HIF1α protein levels were increased. When its levels were high, HIF1α interacted with the Cd36 promoter to augment expression and enhance fatty acid uptake. Thus, these studies establish a novel regulatory link among circadian rhythms, hypoxia response, fatty acid uptake, and NAFLD. The mouse models described here may be useful for further mechanistic studies in the progression of liver diseases and in the discovery of drugs for the treatment of these disorders.
Authors
Xiaoyue Pan, Joyce Queiroz, M. Mahmood Hussain
Abstract
Background. Given the heightened tolerance to self-starvation in anorexia nervosa, a hypothalamic dysregulation of energy and glucose homeostasis has been hypothesized. Therefore, we investigated whether hypothalamic reactivity to glucose metabolism is impaired in AN. Methods. Twenty-four participants with AN, 28 normal-weight and 24 healthy participants with obesity underwent 2 magnetic resonance imaging (MRI) sessions in a single-blind, random-order, case-controlled crossover design. We used an intragastric infusion of glucose and water to bypass the cephalic phase of food intake. The responsivity of the hypothalamus and the crosstalk of the hypothalamus with reward-related brain regions were investigated using high-resolution MRI. Results. Normal-weight control participants displayed the expected glucose-induced deactivation of hypothalamic activation, whereas patients with AN and participants with obesity showed blunted hypothalamic reactivity. Compared to normal-weight and obese controls, patients with AN failed to show functional connectivity between the hypothalamus and reward-related brain regions during water relative to glucose. Finally, patients with AN displayed typical baseline levels of peripheral appetite hormones during a negative energy balance. Conclusion. These results indicate that blunted hypothalamic glucose reactivity might be related to the pathophysiology of AN. This provides new insights for future research, as it is an extended perspective of the traditional primary nonhomeostatic understanding of the disease. Funding. This study was supported by a grant from the DFG (SI 2087/2-1).
Authors
Joe J. Simon, Marion A. Stopyra, Esther Mönning, Sebastian C. A. M. Sailer, Nora Lavandier, Lars Kihm, Martin Bendszus, Hubert Preissl, Wolfgang Herzog, Hans-Christoph Friederich
Abstract
We previously established that global deletion of the enhancer of trithorax and polycomb (ETP) gene, Asxl2, prevents weight gain. Because proinflammatory macrophages recruited to adipose tissue are central to the metabolic complications of obesity, we explored the role of ASXL2 in myeloid lineage cells. Unexpectedly, mice without Asxl2 only in myeloid cells (Asxl2ΔLysM) were completely resistant to diet-induced weight gain and metabolically normal despite increased food intake, comparable activity, and equivalent fecal fat. Asxl2ΔLysM mice resisted HFD-induced adipose tissue macrophage infiltration and inflammatory cytokine gene expression. Energy expenditure and brown adipose tissue metabolism in Asxl2ΔLysM mice were protected from the suppressive effects of HFD, a phenomenon associated with relatively increased catecholamines likely due to their suppressed degradation by macrophages. White adipose tissue of HFD-fed Asxl2ΔLysM mice also exhibited none of the pathological remodeling extant in their control counterparts. Suppression of macrophage Asxl2 expression, via nanoparticle-based siRNA delivery, prevented HFD-induced obesity. Thus, ASXL2 controlled the response of macrophages to dietary factors to regulate metabolic homeostasis, suggesting modulation of the cells’ inflammatory phenotype may impact obesity and its complications.
Authors
Wei Zou, Nidhi Rohatgi, Jonathan R. Brestoff, John R. Moley, Yongjia Li, Jesse W. Williams, Yael Alippe, Hua Pan, Terri A. Pietka, Gabriel Mbalaviele, Elizabeth P. Newberry, Nicholas O. Davidson, Anwesha Dey, Kooresh I. Shoghi, Richard D. Head, Samuel A. Wickline, Gwendalyn J. Randolph, Nada A. Abumrad, Steven L. Teitelbaum
Abstract
Lipid-rich myelin forms electrically insulating, axon-wrapping multilayers that are essential for neural function, and mature myelin is traditionally considered metabolically inert. Surprisingly, we discovered that mature myelin lipids undergo rapid turnover, and quaking (Qki) is a major regulator of myelin lipid homeostasis. Oligodendrocyte-specific Qki depletion, without affecting oligodendrocyte survival, resulted in rapid demyelination, within 1 week, and gradually neurological deficits in adult mice. Myelin lipids, especially the monounsaturated fatty acids and very-long-chain fatty acids, were dramatically reduced by Qki depletion, whereas the major myelin proteins remained intact, and the demyelinating phenotypes of Qki-depleted mice were alleviated by a high-fat diet. Mechanistically, Qki serves as a coactivator of the PPARβ-RXRα complex, which controls the transcription of lipid-metabolism genes, particularly those involved in fatty acid desaturation and elongation. Treatment of Qki-depleted mice with PPARβ/RXR agonists significantly alleviated neurological disability and extended survival durations. Furthermore, a subset of lesions from patients with primary progressive multiple sclerosis were characterized by preferential reductions in myelin lipid contents, activities of various lipid metabolism pathways, and expression level of QKI-5 in human oligodendrocytes. Together, our results demonstrate that continuous lipid synthesis is indispensable for mature myelin maintenance and highlight an underappreciated role of lipid metabolism in demyelinating diseases.
Authors
Xin Zhou, Chenxi He, Jiangong Ren, Congxin Dai, Sharon R. Stevens, Qianghu Wang, Daniel Zamler, Takashi Shingu, Liang Yuan, Chythra R. Chandregowda, Yunfei Wang, Visweswaran Ravikumar, Arvind U.K. Rao, Feng Zhou, Hongwu Zheng, Matthew N. Rasband, Yiwen Chen, Fei Lan, Amy B. Heimberger, Benjamin M. Segal, Jian Hu
Abstract
Prenatal alcohol exposure (PAE) affects at least 10% of newborns globally and leads to the development of fetal alcohol spectrum disorders (FASDs). Despite its high incidence, there is no consensus on the implications of PAE on metabolic disease risk in adults. Here, we describe a cohort of adults with FASDs that had an increased incidence of metabolic abnormalities, including type 2 diabetes, low HDL, high triglycerides, and female-specific overweight and obesity. Using a zebrafish model for PAE, we performed population studies to elucidate the metabolic disease seen in the clinical cohort. Embryonic alcohol exposure (EAE) in male zebrafish increased the propensity for diet-induced obesity and fasting hyperglycemia in adulthood. We identified several consequences of EAE that may contribute to these phenotypes, including a reduction in adult locomotor activity, alterations in visceral adipose tissue and hepatic development, and persistent diet-responsive transcriptional changes. Taken together, our findings define metabolic vulnerabilities due to EAE and provide evidence that behavioral changes and primary organ dysfunction contribute to resultant metabolic abnormalities.
Authors
Olivia Weeks, Gabriel D. Bossé, Isaac M. Oderberg, Sebastian Akle, Yariv Houvras, Paul J. Wrighton, Kyle LaBella, Isabelle Iversen, Sahar Tavakoli, Isaac Adatto, Arkadi Schwartz, Daan Kloosterman, Allison Tsomides, Michael E. Charness, Randall T. Peterson, Matthew L. Steinhauser, Pouneh K. Fazeli, Wolfram Goessling
Influence of adiposity, insulin resistance and intrahepatic triglyceride content on insulin kinetics
Abstract
Background. Insulin is a key regulator of metabolic function. The effects of excess adiposity, insulin resistance and hepatic steatosis on the complex integration of insulin secretion and hepatic and extrahepatic tissue extraction are not clear. Methods. A hyperinsulinemic-euglycemic clamp and a 3-hour oral glucose tolerance test were used to evaluate insulin sensitivity and insulin kinetics after glucose ingestion in three groups: i) lean with normal intrahepatic triglyceride (IHTG) and glucose tolerance (Lean-NL; n=14); ii) obese with normal IHTG and glucose tolerance (Obese-NL; n=24); and iii) obese with hepatic steatosis and prediabetes (Obese-NAFLD; n=22). Results. Insulin sensitivity progressively decreased and insulin secretion progressively increased from Lean-NL to Obese-NL to Obese-NAFLD. Fractional hepatic insulin extraction progressively decreased from Lean-NL to Obese-NL to Obese-NAFLD, whereas total hepatic insulin extraction (molar amount removed) was greater in Obese-NL and Obese-NAFLD than Lean-NL. Insulin appearance in the systemic circulation and extrahepatic insulin extraction progressively increased from Lean-NL to Obese-NL to Obese-NAFLD. Total hepatic insulin extraction plateaued at high rates of insulin delivery, whereas the relationship between systemic insulin appearance and total extrahepatic extraction was linear. Conclusion. Hyperinsulinemia after glucose ingestion in Obese-NL and Obese-NAFLD is due to an increase in insulin secretion, without a decrease in total hepatic or extrahepatic insulin extraction. However, the liver’s maximum capacity to remove insulin is limited because of a saturable extraction process. The increase in insulin delivery to the liver and extrahepatic tissues in Obese-NAFLD is unable to compensate for the increase in insulin resistance, resulting in impaired glucose homeostasis.
Authors
Gordon I. Smith, David C. Polidori, Mihoko Yoshino, Monica L. Kearney, Bruce W. Patterson, Bettina Mittendorfer, Samuel Klein
Abstract
Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the CNS. Bile acids are cholesterol metabolites that can signal through receptors on cells throughout the body, including the CNS and immune system. Whether bile acid metabolism is abnormal in MS is unknown. Using global and targeted metabolomic profiling, we identified lower levels of circulating bile acid metabolites in multiple cohorts of adult and pediatric MS patients compared to controls. In white matter lesions from MS brain tissue, we noted the presence of bile acid receptors on immune and glial cells. To mechanistically examine the implications of lower levels of bile acids in MS, we studied the in vitro effects of an endogenous bile acid – tauroursodeoxycholic acid (TUDCA) on astrocyte and microglial polarization. TUDCA prevented neurotoxic (A1) polarization of astrocytes and pro-inflammatory polarization of microglia in a dose-dependent manner. TUDCA supplementation in experimental autoimmune encephalomyelitis reduced severity of disease through its effects on GPBAR1, based on behavioral and pathological measures. We demonstrate that bile acid metabolism is altered in MS; bile acid supplementation prevents polarization of astrocytes and microglia to neurotoxic phenotypes and ameliorates neuropathology in an animal model of MS. These findings identify dysregulated bile acid metabolism as a potential therapeutic target in MS.
Authors
Pavan Bhargava, Matthew D. Smith, Leah Mische, Emily P. Harrington, Kathryn C. Fitzgerald, Kyle A. Martin, Sol Kim, Arthur Anthony A. Reyes, Jaime Gonzalez-Cardona, Christina Volsko, Ajai Tripathi, Sonal Singh, Kesava Varanasi, Hannah-Noelle Lord, Keya R. Meyers, Michelle Taylor, Marjan Gharagozloo, Elias S. Sotirchos, Bardia Nourbakhsh, Ranjan Dutta, Ellen Mowry, Emmanuelle Waubant, Peter A. Calabresi
Abstract
β-cell apoptosis and dedifferentiation are two hotly-debated mechanisms underlying β-cell loss in type 2 diabetes; however, the molecular drivers underlying such events remain largely unclear. Here, we performed a side-by-side comparison of mice carrying β-cell-specific deletion of endoplasmic reticulum (ER)-associated degradation (ERAD) and autophagy. We reported that while autophagy was necessary for β-cell survival, the highly conserved Sel1L-Hrd1 ERAD protein complex was required for the maintenance of β-cell maturation and identity. Using single cell RNA-sequencing, we demonstrated that Sel1L deficiency was not associated with β-cell loss, but rather loss of β-cell identity. Sel1L-Hrd1 ERAD controlled β-cell identity via TGFβ signaling, in part by mediating the degradation of TGFβ receptor 1 (TGFβRI). Inhibition of TGFβ signaling in Sel1L-deficient β-cells augmented the expression of β-cell maturation markers and increased the total insulin content. Our data revealed distinct pathogenic effects of two major proteolytic pathways in β-cells, providing a new framework for therapies targeting distinct mechanisms of protein quality control.
Authors
Neha Shrestha, Tongyu Liu, Yewei Ji, Rachel Reinert, Mauricio Torres, Xin Li, Maria Zhang, Chih-Hang Anthony Tang, Chih-Chi Andrew Hu, Chengyang Liu, Ali Naji, Ming Liu, Jiandie D. Lin, Sander Kersten, Peter Arvan, Ling Qi
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)