Biochemical Phenomena, Metabolism, and Nutrition Commons^™

Limosilactobacillus Reuteri Alleviates Proinflammatory T-Cell-Mediated Liver Injury And Transcriptomic Changes In Immunocompromised Mice, Ana Fadhel Alvarez, Zheng Yin, Beanna Okeugo, Alexander Banerjee, Meng Luo, Christopher M Taylor, Salomea Giorgberidze, Vaishali Harne, Rambabu Majji, Melissa N Munroe, Ji Ho Suh, Stephen T C Wong, Kang Ho Kim, Hari Krishna Yalamanchili, Suhair Al Salihi, Jon Marc Rhoads, Yuying Liu

Children’s Nutrition Research Center Staff Publications

Background: A deficiency of immunosuppressive regulatory T cells, as seen in scurfy (SF) mice or in IPEX syndrome in humans, can lead to multiorgan inflammation. Oral administration of the probiotic Limosilactobacillus reuteri Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSM) 17938 prolongs survival and reduces Th1- and Th2-associated inflammation in SF mice. It remains unclear how DSM 17938-educated SF-CD4+ T cells modulate T-cell-liver communication.

Methods: To characterize CD4+ T cells from SF mice orally administered DSM 17938 (Prob-SF-CD4+ T cells) and to compare them with CD4+ T cells from SF mice (SF-CD4+ T cells), cells isolated from SF spleens were …

N-Acetylaspartate From Fat Cells Regulates Postprandial Body Temperature, Jessica B Felix, Pradip K Saha, Evelyn L De Groot, Lin Tan, Robert Sharp, Elizabeth S Anaya, Yafang Li, Holly Quang, Nooshin Saidi, Layla Abushamat, Christie M Ballantyne, Christopher I Amos, Philip L Lorenzi, Samuel Klein, Xia Gao, Sean M Hartig

Faculty, Staff and Students Publications

N-acetylaspartate (NAA), the brain’s second most abundant metabolite, provides essential substrates for myelination through its hydrolysis1. However, the physiological roles of NAA in other tissues remain unknown. Here, we show that aspartoacylase (ASPA) expression in white adipose tissue (WAT) governs blood NAA levels for postprandial body temperature regulation. Genetic ablation of Aspa in mice resulted in systemically elevated NAA levels, and the ensuing accumulation in WAT stimulated pyrimidine production. Stable isotope tracing confirmed higher incorporation of glucose-derived carbon into pyrimidine metabolites in Aspa knockout cells. Additionally, serum NAA levels positively correlated with the abundance of the pyrimidine …

Functional Regulation Of Macrophages By Ces1d-Mediated Lipid Signaling In Immunometabolism, Long J Shao, Fathima Elizondo, Feng Gao, Rabie Habib, Xin Li, Katherine Pham, Jazmin Ysaguirre, Maryam Elizondo, Shirindokht Shirazi, Kristin L Eckel-Mahan, Sean Hartig, Huaizhu Wu, Kai Sun

Faculty, Staff and Student Publications

Objective: Macrophage accumulation in metabolically active tissues during obesity is common in both animals and humans, but the lipid signaling mechanisms that trigger macrophage inflammation remain unclear. This study investigates the role of Ces1d, an unconventional lipase, in regulating macrophage inflammation under nutritional stress.

Methods: A myeloid-specific Ces1d knockout (LysM-Cre-Ces1d floxed/floxed, KO) mouse model was used for the studies. For in vitro tests, bone marrow-derived macrophages (BMDMs) from control (Ces1d floxed/floxed, WT) and KO mice were assessed for migration, polarization, and activation. For in vivo experiments, WT and KO mice were induced to obesity via a high-fat diet (HFD) and …

Muscle Rev-Erb Controls Time-Dependent Adaptations To Chronic Exercise In Mice, Jidong Liu, Fang Xiao, Abhinav Choubey, Udhaya Kumar S, Yanxiang Wang, Sungguan Hong, Tingting Yang, Husniye Gul Otlu, Ege Sanem Oturmaz, Emanuele Loro, Yuxiang Sun, Pradip Saha, Tejvir S Khurana, Li Chen, Xinguo Hou, Zheng Sun

Center on Aging Staff Publications

The best time of the day for chronic exercise training and the mechanism underlying the timing effects is unclear. Here, we show that low-intensity, low-volume treadmill training in mice before sleep yields greater benefits than after waking for muscle contractile performance and systemic glucose tolerance. Baseline muscle performance also exhibits diurnal variations, with higher strength but lower endurance before sleep than after waking. Muscle-specific knockout of circadian clock genes Rev-erbα/β (Rev-MKO) in male mice eradicates the diurnal variations in both training and baseline conditions without affecting muscle mass, mitochondrial content, food intake, or spontaneous activities. Multi-omics and metabolic measurements reveal …

Changes In The Fxr-Cistrome And Alterations In Bile Acid Physiology In Wilson Disease, Clavia Ruth Wooton-Kee, Hari K Yalamanchili, Islam Mohamed, Manal Hassan, Kenneth D R Setchell, Monica Narvaez Rivas, Ayse K Coskun, Vasanta Putluri, Nagireddy Putluri, Prasun Jalal, Michael L Schilsky, David D Moore

Children’s Nutrition Research Center Staff Publications

Background: Wilson disease (WD) is an autosomal recessive disorder that results in excessive hepatic copper, causing hepatic steatosis, inflammation, fibrosis, cirrhosis, and liver failure. Previous studies have revealed dysregulation of many farnesoid X receptor (FXR) metabolic target genes in WD, including the bile salt exporter pump, the major determinant of bile flow.

Methods: We tested the hypothesis that the FXR-cistrome is decreased in Atp7b-/- mice in accord with dysregulated bile acid homeostasis.

Results: FXR binding within Atp7b-/- mouse livers displayed surprising complexity: FXR binding was increased in distal intergenic regions but decreased in promoter regions in Atp7b-/- versus wild-type mice. …

The Small Gtpase Rap1 In Pomc Neurons Regulates Leptin Actions And Glucose Metabolism, Kentaro Kaneko, Weisheng Lu, Yong Xu, Alexei Morozov, Makoto Fukuda

Faculty, Staff and Students Publications

The hypothalamic leptin-proopiomelanocortin (POMC) pathway is critical for regulating metabolism. POMC neurons in the arcuate nucleus respond to leptin and play a pivotal role in mediating energy and glucose balance. However, during diet-induced obesity (DIO), these neurons often develop resistance to exogenous leptin. Recently, the small GTPase Rap1 has been implicated as an inhibitor of neuronal leptin signaling; however, its specific role within POMC neurons remains unexplored. We generated tamoxifen-inducible, POMC neuron-specific Rap1 knockout mice to selectively delete both Rap1a and Rap1b isoforms in POMC neurons. By analyzing these mice through metabolic phenotyping, immunohistochemistry, and biochemical assays, we show that …

Altered Thermal Preference By Preoptic Estrogen Receptor Alpha Neurons In Postpartum Females, Nan Zhang, Meng Yu, Qianru Zhao, Bing Feng, Yue Deng, Jonathan C Bean, Qingzhuo Liu, Benjamin P Eappen, Yang He, Kristine M Conde, Hailan Liu, Yongjie Yang, Longlong Tu, Mengjie Wang, Yongxiang Li, Na Yin, Hesong Liu, Junying Han, Darah Ave Threat, Nathan Xu, Taylor Smiley, Pingwen Xu, Lulu Chen, Tianshu Zeng, Yanlin He, Chunmei Wang

Faculty, Staff and Students Publications

OBJECTIVE: This study aims to investigate how reproductive experience (RE) alters thermal preference and thermoregulation in female mice, with a focus on estrogen receptor alpha (ERα)-expressing neurons in the preoptic area (POA).

METHODS: Thermal preference and body temperature were measured in female mice with and without RE, and virgin female mice with selective deletion of ERα from the POA (ERα

RESULTS: We showed that female mice prefer a cooler environment starting from late pregnancy and persisting long term postpartum. Female mice with RE (>4 weeks post-weaning) displayed lower body temperature and a lower thermal preferred temperature, and lost preference …

A Β-Hydroxybutyrate Shunt Pathway Generates Anti-Obesity Ketone Metabolites, Maria Dolores Moya-Garzon, Mengjie Wang, Veronica L Li, Xuchao Lyu, Wei Wei, Alan Sheng-Hwa Tung, Steffen H Raun, Meng Zhao, Laetitia Coassolo, Hashim Islam, Barbara Oliveira, Yuqin Dai, Jan Spaas, Antonio Delgado-Gonzalez, Kenyi Donoso, Aurora Alvarez-Buylla, Francisco Franco-Montalban, Anudari Letian, Catherine P Ward, Lichao Liu, Katrin J Svensson, Emily L Goldberg, Christopher D Gardner, Jonathan P Little, Steven M Banik, Yong Xu, Jonathan Z Long

Children’s Nutrition Research Center Staff Publications

β-Hydroxybutyrate (BHB) is an abundant ketone body. To date, all known pathways of BHB metabolism involve the interconversion of BHB and primary energy intermediates. Here, we identify a previously undescribed BHB secondary metabolic pathway via CNDP2-dependent enzymatic conjugation of BHB and free amino acids. This BHB shunt pathway generates a family of anti-obesity ketone metabolites, the BHB-amino acids. Genetic ablation of CNDP2 in mice eliminates tissue amino acid BHB-ylation activity and reduces BHB-amino acid levels. The most abundant BHB-amino acid, BHB-Phe, is a ketosis-inducible congener of Lac-Phe that activates hypothalamic and brainstem neurons and suppresses feeding. Conversely, CNDP2-KO mice exhibit …

The Dna Demethylase Tet1 Modifies The Impact Of Maternal Folic Acid Status On Embryonic Brain Development, Lehua Chen, Bernard K Van Der Veer, Qiuying Chen, Spyridon Champeris Tsaniras, Wannes Brangers, Harm H M Kwak, Rita Khoueiry, Yunping Lei, Robert Cabrera, Steven S Gross, Richard H Finnell, Kian Peng Koh

Faculty, Staff and Students Publications

Folic acid (FA) is well known to prevent neural tube defects (NTDs), but we do not know why many human NTD cases still remain refractory to FA supplementation. Here, we investigate how the DNA demethylase TET1 interacts with maternal FA status to regulate mouse embryonic brain development. We determined that cranial NTDs display higher penetrance in non-inbred than in inbred Tet1−/− embryos and are resistant to FA supplementation across strains. Maternal diets that are either too rich or deficient in FA are linked to an increased incidence of cranial deformities in wild type and Tet1+/− offspring and to …

Mechanistic Insights Into Metabolic Function Of Dynamin-Related Protein 1, Xin Li, Katherine Pham, Jazmin Ysaguirre, Iqbal Mahmud, Lin Tan, Bo Wei, Long J Shao, Maryam Elizondo, Rabie Habib, Fathima Elizondo, Hiromi Sesaki, Philip L Lorenzi, Kai Sun

Faculty, Staff and Student Publications

Dynamin-related protein 1 (DRP1) plays crucial roles in mitochondrial and peroxisome fission. However, the mechanisms underlying the functional regulation of DRP1 in adipose tissue during obesity remain unclear. To elucidate the metabolic and pathological significance of diminished DRP1 in obese adipose tissue, we utilized adipose tissue-specific DRP1 KO mice challenged with a high-fat diet. We observed significant metabolic dysregulations in the KO mice. Mechanistically, DRP1 exerts multifaceted functions in mitochondrial dynamics and endoplasmic reticulum (ER)-lipid droplet crosstalk in normal mice. Loss of function of DRP1 resulted in abnormally giant mitochondrial shapes, distorted mitochondrial membrane structure, and disrupted cristae architecture. Meanwhile, …

Deletion Of Mipep In Adipocytes Protects Against Obesity And Insulin Resistance By Boosting Muscle Metabolism, Alexis Diaz-Vegas, Kristen C Cooke, Harry B Cutler, Belinda Yau, Stewart W C Masson, Dylan Harney, Oliver K Fuller, Meg Potter, Søren Madsen, Niamh R Craw, Yiju Zhang, Cesar L Moreno, Melkam A Kebede, G Gregory Neely, Jacqueline Stöckli, James G Burchfield, David E James

Faculty, Staff and Students Publications

Mitochondria facilitate thousands of biochemical reactions, covering a broad spectrum of anabolic and catabolic processes. Here we demonstrate that the adipocyte mitochondrial proteome is markedly altered across multiple models of insulin resistance and reveal a consistent decrease in the level of the mitochondrial processing peptidase miPEP.

OBJECTIVE: To determine the role of miPEP in insulin resistance.

METHODS: To experimentally test this observation, we generated adipocyte-specific miPEP knockout mice to interrogate its role in the aetiology of insulin resistance.

RESULTS: We observed a strong phenotype characterised by enhanced insulin sensitivity and reduced adiposity, despite normal food intake and physical activity. Strikingly, …

Dose-Dependent Effects Of Dnmt3a In An Inducible Murine Model Of Krasg12d-Driven Leukemia, Jason H Rogers, Allison Rosen, Jaime M Reyes, Shamika Ketkar, Shannon E Conneely, Rohit Gupta, Luibin Yang, Matthew B Miller, Geraldo Medrano, Rogelio Aguilar, Nneka Uchenda, Margaret A Goodell, Rachel E Rau

Children’s Nutrition Research Center Staff Publications

DNMT3A mutations are frequently found in clonal hematopoiesis and a variety of hematologic malignancies including acute myeloid leukemia (AML). An assortment of mouse models have been engineered to explore the tumorigenic potential and malignant lineage bias due to loss of function of DNMT3A in consort with commonly co-mutated genes in myeloid malignancies such as Flt3, Nras, Kras, and c-Kit. We employed several tamoxifen-inducible Cre-ER^T2 murine model systems to study the effects of constitutively active Kras^G12D-driven myeloid leukemia (Kras) development together with heterozygous (3aHet) or homozygous Dnmt3a deletion (3aKO). Due to the rapid generation of …

Mesenchymal-Specific Alms1 Knockout In Mice Recapitulates Metabolic Features Of Alström Syndrome, Eleanor J Mckay, Ineke Luijten, Xiong Weng, Pablo B Martinez De Morentin, Elvira De Frutos González, Zhanguo Gao, Mikhail G Kolonin, Lora K Heisler, Robert K Semple

Faculty, Staff and Student Publications

OBJECTIVE: Alström Syndrome (AS), caused by biallelic ALMS1 mutations, includes obesity with disproportionately severe insulin resistant diabetes, dyslipidemia, and fatty liver. Prior studies suggest that hyperphagia is accounted for by loss of ALMS1 function in hypothalamic neurones, whereas disproportionate metabolic complications may be due to impaired adipose tissue expandability. We tested this by comparing the metabolic effects of global and mesenchymal stem cell (MSC)-specific Alms1 knockout.

METHODS: Global Alms1 knockout (KO) mice were generated by crossing floxed Alms1 and CAG-Cre mice. A Pdgfrα-Cre driver was used to abrogate Alms1 function selectively in MSCs and their descendants, including preadipocytes. We combined …

Mitochondria Regulate Proliferation In Adult Cardiac Myocytes, Gregory B Waypa, Kimberly A Smith, Paul T Mungai, Vincent J Dudley, Kathryn A Helmin, Benjamin D Singer, Clara Bien Peek, Joseph Bass, Lauren Nelson, Sanjiv J Shah, Gaston Ofman, J Andrew Wasserstrom, William A Muller, Alexander V Misharin, G R Scott Budinger, Hiam Abdala-Valencia, Navdeep S Chandel, Danijela Dokic, Elizabeth Bartom, Shuang Zhang, Yuki Tatekoshi, Amir Mahmoodzadeh, Hossein Ardehali, Edward B Thorp, Paul T Schumacker

Faculty, Staff and Student Publications

Newborn mammalian cardiomyocytes quickly transition from a fetal to an adult phenotype that utilizes mitochondrial oxidative phosphorylation but loses mitotic capacity. We tested whether forced reversal of adult cardiomyocytes back to a fetal glycolytic phenotype would restore proliferative capacity. We deleted Uqcrfs1 (mitochondrial Rieske iron-sulfur protein, RISP) in hearts of adult mice. As RISP protein decreased, heart mitochondrial function declined, and glucose utilization increased. Simultaneously, the hearts underwent hyperplastic remodeling during which cardiomyocyte number doubled without cellular hypertrophy. Cellular energy supply was preserved, AMPK activation was absent, and mTOR activation was evident. In ischemic hearts with RISP deletion, new cardiomyocytes …

An Estrogen Receptor Α-Derived Peptide Improves Glucose Homeostasis During Obesity, Wanbao Yang, Wen Jiang, Wang Liao, Hui Yan, Weiqi Ai, Quan Pan, Wesley A Brashear, Yong Xu, Ling He, Shaodong Guo

Faculty, Staff and Students Publications

Estrogen receptor α (ERα) plays a crucial role in regulating glucose and energy homeostasis during type 2 diabetes mellitus (T2DM). However, the underlying mechanisms remain incompletely understood. Here we find a ligand-independent effect of ERα on the regulation of glucose homeostasis. Deficiency of ERα in the liver impairs glucose homeostasis in male, female, and ovariectomized (OVX) female mice. Mechanistic studies reveal that ERα promotes hepatic insulin sensitivity by suppressing ubiquitination-induced IRS1 degradation. The ERα 1-280 domain mediates the ligand-independent effect of ERα on insulin sensitivity. Furthermore, we identify a peptide based on ERα 1-280 domain and find that ERα-derived peptide …

Endogenous Renal Adiponectin Drives Gluconeogenesis Through Enhancing Pyruvate And Fatty Acid Utilization, Toshiharu Onodera, May-Yun Wang, Joseph M Rutkowski, Stanislaw Deja, Shiuhwei Chen, Michael S Balzer, Dae-Seok Kim, Xuenan Sun, Yu A An, Bianca C Field, Charlotte Lee, Ei-Ichi Matsuo, Monika Mizerska, Ina Sanjana, Naoto Fujiwara, Christine M Kusminski, Ruth Gordillo, Laurent Gautron, Denise K Marciano, Ming Chang Hu, Shawn C Burgess, Katalin Susztak, Orson W Moe, Philipp E Scherer

Faculty, Staff and Student Publications

Adiponectin is a secretory protein, primarily produced in adipocytes. However, low but detectable expression of adiponectin can be observed in cell types beyond adipocytes, particularly in kidney tubular cells, but its local renal role is unknown. We assessed the impact of renal adiponectin by utilizing male inducible kidney tubular cell-specific adiponectin overexpression or knockout mice. Kidney-specific adiponectin overexpression induces a doubling of phosphoenolpyruvate carboxylase expression and enhanced pyruvate-mediated glucose production, tricarboxylic acid cycle intermediates and an upregulation of fatty acid oxidation (FAO). Inhibition of FAO reduces the adiponectin-induced enhancement of glucose production, highlighting the role of FAO in the induction …

In Vivo Functional Characterization Of Egfr Variants Identifies Novel Drivers Of Glioblastoma, Kwanha Yu, Kathleen Kong, Brittney Lozzi, Estefania Luna-Figueroa, Alexis Cervantes, Rachel Curry, Carrie A Mohila, Ganesh Rao, Ali Jalali, Gordon B Mills, Kenneth L Scott, Benjamin Deneen

Faculty, Staff and Students Publications

BACKGROUND: Glioblastoma is the most common and aggressive primary brain tumor. Large-scale sequencing initiatives have cataloged its mutational landscape in hopes of elucidating mechanisms driving this deadly disease. However, a major bottleneck in harnessing this data for new therapies is deciphering "driver" and "passenger" events amongst the vast volume of information.

METHODS: We utilized an autochthonous, in vivo screening approach to identify driver, EGFR variants. RNA-Seq identified unique molecular signatures of mouse gliomas across these variants, which only differ by a single amino acid change. In particular, we identified alterations to lipid metabolism, which we further validated through an unbiased …

Dual-Specificity Phosphatases 22-Deficient T Cells Contribute To The Pathogenesis Of Ankylosing Spondylitis, Ming-Han Chen, Huai-Chia Chuang, Yi-Chen Yeh, Chung-Tei Chou, Tse-Hua Tan

Children’s Nutrition Research Center Staff Publications

Background: Dual-specificity phosphatases (DUSPs) can dephosphorylate both tyrosine and serine/threonine residues of their substrates and regulate T cell-mediated immunity and autoimmunity. The aim of this study was to investigate the potential roles of DUSPs in ankylosing spondylitis (AS).

Methods: Sixty AS patients and 45 healthy controls were enrolled in this study. Associations of gene expression of 23 DUSPs in peripheral T cells with inflammatory cytokine gene expression and disease activity of AS were analyzed. Finally, we investigated whether the characteristics of AS are developed in DUSP-knockout mice.

Results: The mRNA levels of DUSP4, DUSP5, DUSP6, DUSP7, and DUSP14 in peripheral …

The Roles Of Cyp1a2 And Cyp2d In Pharmacokinetic Profiles Of Serotonin And Norepinephrine Reuptake Inhibitor Duloxetine And Its Metabolites In Mice, Xuan Qin, Cen Xie, John M Hakenjos, Kevin R Mackenzie, Shelton R Boyd, Mercedes Barzi, Karl-Dimiter Bissig, Damian W Young, Feng Li

Faculty, Staff and Students Publications

Duloxetine (DLX) is widely used to treat major depressive disorder. Little is known about the mechanistic basis for DLX-related adverse effects (e.g., liver injury). Human CYP1A2 and CYP2D6 mainly contributes to DLX metabolism, which was proposed to be involved in its adverse effects. Here, we investigated the roles of Cyp1a2 and Cyp2d on DLX pharmacokinetic profile and tissue distribution using a Cyp1a2 knockout (Cyp1a2-KO) mouse model together with a Cyp2d inhibitor (propranolol). Cyp1a2-KO has the few effects on the systematic exposure (area under the plasma concentration-time curve, AUC) and tissue disposition of DLX and its primary metabolites. Propranolol dramatically increased …

Myocardial Rev-Erb-Mediated Diurnal Metabolic Rhythm And Obesity Paradox, Shiyang Song, Chih-Liang Tien, Hao Cui, Paul Basil, Ningxia Zhu, Yingyun Gong, Wenbo Li, Hui Li, Qiying Fan, Jong Min Choi, Weijia Luo, Yanfeng Xue, Rui Cao, Wenjun Zhou, Andrea R Ortiz, Brittany Stork, Vatsala Mundra, Nagireddy Putluri, Brian York, Maoping Chu, Jiang Chang, Sung Yun Jung, Liang Xie, Jiangping Song, Lilei Zhang, Zheng Sun

Faculty, Staff and Students Publications

BACKGROUND: The nuclear receptor Rev-erbα/β, a key component of the circadian clock, emerges as a drug target for heart diseases, but the function of cardiac Rev-erb has not been studied in vivo. Circadian disruption is implicated in heart diseases, but it is unknown whether cardiac molecular clock dysfunction is associated with the progression of any naturally occurring human heart diseases. Obesity paradox refers to the seemingly protective role of obesity for heart failure, but the mechanism is unclear.

METHODS: We generated mouse lines with cardiac-specific Rev-erbα/β knockout (KO), characterized cardiac phenotype, conducted multi-omics (RNA-sequencing, chromatin immunoprecipitation sequencing, proteomics, and metabolomics) …

Gαi/O-Coupled Htr2c In The Paraventricular Nucleus Of The Hypothalamus Antagonizes The Anorectic Effect Of Serotonin Agents, Eun-Seon Yoo, Li Li, Lin Jia, Caleb C Lord, Charlotte E Lee, Shari G Birnbaum, Claudia R Vianna, Eric D Berglund, Kathryn A Cunningham, Yong Xu, Jong-Woo Sohn, Chen Liu

Children’s Nutrition Research Center Staff Publications

The anorexigenic effect of serotonergic compounds has largely been attributed to activation of serotonin 2C receptors (Htr2cs). Using mouse genetic models in which Htr2c can be selectively deleted or restored (in Htr2c-null mice), we investigate the role of Htr2c in forebrain Sim1 neurons. Unexpectedly, we find that Htr2c acts in these neurons to promote food intake and counteract the anorectic effect of serotonergic appetite suppressants. Furthermore, Htr2c marks a subset of Sim1 neurons in the paraventricular nucleus of the hypothalamus (PVH). Chemogenetic activation of these neurons in adult mice suppresses hunger, whereas their silencing promotes feeding. In …

Endothelium-Specific Depletion Of Lrp1 Improves Glucose Homeostasis Through Inducing Osteocalcin, Hua Mao, Luge Li, Qiying Fan, Aude Angelini, Pradip K Saha, Cristian Coarfa, Kimal Rajapakshe, Dimuthu Perera, Jizhong Cheng, Huaizhu Wu, Christie M Ballantyne, Zheng Sun, Liang Xie, Xinchun Pi

Faculty, Staff and Students Publications

The vascular endothelium is present within metabolic organs and actively regulates energy metabolism. Here we show osteocalcin, recognized as a bone-secreted metabolic hormone, is expressed in mouse primary endothelial cells isolated from heart, lung and liver. In human osteocalcin promoter-driven green fluorescent protein transgenic mice, green fluorescent protein signals are enriched in endothelial cells lining aorta, small vessels and capillaries and abundant in aorta, skeletal muscle and eye of adult mice. The depletion of lipoprotein receptor-related protein 1 induces osteocalcin through a Forkhead box O -dependent pathway in endothelial cells. Whereas depletion of osteocalcin abolishes the glucose-lowering effect of low-density …

Ube2i Deletion In Adipocytes Causes Lipoatrophy In Mice, Aaron R Cox, Natasha Chernis, Kang Ho Kim, Peter M Masschelin, Pradip K Saha, Shawn M Briley, Robert Sharp, Xin Li, Jessica B Felix, Zheng Sun, David D Moore, Stephanie A Pangas, Sean M Hartig

Faculty, Staff and Students Publications

OBJECTIVE: White adipose tissue (WAT) expansion regulates energy balance and overall metabolic homeostasis. The absence or loss of WAT occurring through lipodystrophy and lipoatrophy contributes to the development of hepatic steatosis and insulin resistance. We previously demonstrated that sole small ubiquitin-like modifier (SUMO) E2-conjugating enzyme Ube2i represses human adipocyte differentiation. The role of Ube2i during WAT development remains unknown.

METHODS: To determine how Ube2i impacts body composition and energy balance, we generated adipocyte-specific Ube2i knockout mice (Ube2i

RESULTS: Surprisingly, Ube2i

CONCLUSIONS: Our results demonstrate that Ube2i expression in mature adipocytes allows WAT expansion during postnatal growth. Deletion of Ube2i in …

Sirt3 Is Required For Liver Regeneration But Not For The Beneficial Effect Of Nicotinamide Riboside, Sarmistha Mukherjee, James Mo, Lauren M Paolella, Caroline E Perry, Jade Toth, Mindy M Hugo, Qingwei Chu, Qiang Tong, Karthikeyani Chellappa, Joseph A Baur

Children’s Nutrition Research Center Staff Publications

Liver regeneration is critical to survival after traumatic injuries, exposure to hepatotoxins, or surgical interventions, yet the underlying signaling and metabolic pathways remain unclear. In this study, we show that hepatocyte-specific loss of the mitochondrial deacetylase SIRT3 drastically impairs regeneration and worsens mitochondrial function after partial hepatectomy. Sirtuins, including SIRT3, require NAD as a cosubstrate. We previously showed that the NAD precursor nicotinamide riboside (NR) promotes liver regeneration, but whether this involves sirtuins has not been tested. Here, we show that despite their NAD dependence and critical roles in regeneration, neither SIRT3 nor its nuclear counterpart SIRT1 is required for …

Loss Of Bone Morphogenetic Protein-Binding Endothelial Regulator Causes Insulin Resistance, Hua Mao, Luge Li, Qiying Fan, Aude Angelini, Pradip K Saha, Huaizhu Wu, Christie M Ballantyne, Sean M Hartig, Liang Xie, Xinchun Pi

Faculty, Staff and Students Publications

Accumulating evidence suggests that chronic inflammation of metabolic tissues plays a causal role in obesity-induced insulin resistance. Yet, how specific endothelial factors impact metabolic tissues remains undefined. Bone morphogenetic protein (BMP)–binding endothelial regulator (BMPER) adapts endothelial cells to inflammatory stress in diverse organ microenvironments. Here, we demonstrate that BMPER is a driver of insulin sensitivity. Both global and endothelial cell-specific inducible knockout of BMPER cause hyperinsulinemia, glucose intolerance and insulin resistance without increasing inflammation in metabolic tissues in mice. BMPER can directly activate insulin signaling, which requires its internalization and interaction with Niemann-Pick C1 (NPC1), an integral membrane protein that …

Vertical Sleeve Gastrectomy Confers Metabolic Improvements By Reducing Intestinal Bile Acids And Lipid Absorption In Mice, Lili Ding, Eryun Zhang, Qiaoling Yang, Lihua Jin, Kyle M Sousa, Bingning Dong, Yangmeng Wang, Jui Tu, Xiaoxiao Ma, Jingyan Tian, Hongli Zhang, Zhipeng Fang, Ana Guan, Yixin Zhang, Zhengtao Wang, David D Moore, Li Yang, Wendong Huang

Faculty, Staff and Students Publications

Vertical sleeve gastrectomy (VSG) is a highly effective bariatric surgery that sustainably treats obesity and type 2 diabetes (T2D). However, the underlying mechanisms governing its metabolic benefits remain unclear. In this study, we have used four different genetically modified mouse lines to understand the link between bile acid circulation and metabolic effects of VSG. Instead of directly activating the nuclear bile acid receptor farnesoid X receptor (Fxr) in the liver or intestine, VSG reduces intestinal levels of bile acids, thereby decreasing fat absorption in the intestine. Given the rising popularity of bariatric surgeries to treat obesity and associated T2D, the …

Crucial Role Of Mammalian Glutaredoxin 3 In Cardiac Energy Metabolism In Diet-Induced Obese Mice Revealed By Transcriptome Analysis, Ninghui Cheng, Qianxing Mo, Jimmonique Donelson, Lingfei Wang, Ghislain Breton, George G Rodney, Jin Wang, Kendal D Hirschi, Xander H T Wehrens, Paul A Nakata

Children’s Nutrition Research Center Staff Publications

Obesity is often associated with metabolic dysregulation and oxidative stress with the latter serving as a possible unifying link between obesity and cardiovascular complications. Glutaredoxins (Grxs) comprise one of the major antioxidant systems in the heart. Although Grx3 has been shown to act as an endogenous negative regulator of cardiac hypertrophy and heart failure, its metabolic impact on cardiac function in diet-induced obese (DIO) mice remains largely unknown. In the present study, analysis of Grx3 expression indicated that Grx3 protein levels, but not mRNA levels, were significantly increased in the hearts of DIO mice. Cardiac-specific Grx3 deletion (Grx3 CKO) mice …

Tph2 In The Dorsal Raphe Nuclei Regulates Energy Balance In A Sex-Dependent Manner, Hailan Liu, Chunmei Wang, Meng Yu, Yongjie Yang, Yang He, Hesong Liu, Chen Liang, Longlong Tu, Nan Zhang, Lina Wang, Julia Wang, Feng Liu, Fang Hu, Yong Xu

Children’s Nutrition Research Center Staff Publications

AbstractCentral 5-hydroxytryptamine (5-HT), which is primarily synthesized by tryptophan hydroxylase 2 (TPH2) in the dorsal Raphe nuclei (DRN), plays a pivotal role in the regulation of food intake and body weight. However, the physiological functions of TPH2 on energy balance have not been consistently demonstrated. Here we systematically investigated the effects of TPH2 on energy homeostasis in adult male and female mice. We found that the DRN harbors a similar amount of TPH2+ cells in control male and female mice. Adult-onset TPH2 deletion in the DRN promotes hyperphagia and body weight gain only in male mice, but not in female …

Adaptive Thermogenesis Enhances The Life-Threatening Response To Heat In Mice With An Ryr1 Mutation, Hui J Wang, Chang Seok Lee, Rachel Sue Zhen Yee, Linda Groom, Inbar Friedman, Lyle Babcock, Dimitra K Georgiou, Jin Hong, Amy D Hanna, Joseph Recio, Jong Min Choi, Ting Chang, Nadia H Agha, Jonathan Romero, Poonam Sarkar, Nicol Voermans, M Waleed Gaber, Sung Yun Jung, Matthew L Baker, Robia G Pautler, Robert T Dirksen, Sheila Riazi, Susan L Hamilton

Faculty, Staff and Students Publications

Mutations in the skeletal muscle Ca2+ release channel, the type 1 ryanodine receptor (RYR1), cause malignant hyperthermia susceptibility (MHS) and a life-threatening sensitivity to heat, which is most severe in children. Mice with an MHS-associated mutation in Ryr1 (Y524S, YS) display lethal muscle contractures in response to heat. Here we show that the heat response in the YS mice is exacerbated by brown fat adaptive thermogenesis. In addition, the YS mice have more brown adipose tissue thermogenic capacity than their littermate controls. Blood lactate levels are elevated in both heat-sensitive MHS patients with RYR1 mutations and YS mice due to …

Mtor-Initiated Metabolic Switch And Degeneration In The Retinal Pigment Epithelium, Young-Mi Go, Jing Zhang, Jolyn Fernandes, Christopher Litwin, Rui Chen, Theodore G Wensel, Dean P Jones, Jiyang Cai, Yan Chen

Faculty, Staff and Students Publications

The retinal pigment epithelium (RPE) is a particularly vulnerable tissue to age-dependent degeneration. Over the life span, the RPE develops an expanded endo-lysosomal compartment to maintain the high efficiency of phagocytosis and degradation of photoreceptor outer segments (POS) necessary for photoreceptor survival. As the assembly and activation of the mechanistic target of rapamycin complex 1 (mTORC1) occur on the lysosome surface, increased lysosome mass with aging leads to higher mTORC1 activity. The functional consequences of hyperactive mTORC1 in the RPE are unclear. In the current study, we used integrated high-resolution metabolomic and genomic approaches to examine mice with RPE-specific deletion …