THE ROLE OF HEPATOKINE ORM2 IN ADIPOSE TISSUE INFLAMMATION

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: Kangho  Kim
Organization: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
Fiscal Year: 2024
Award: $374,400
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases

ABSTRACT
Bile acids (BAs) have recently emerged as metabolic regulators in obesity and type 2 diabetes. We discovered
that the BA overload in farnesoid X receptor (FXR) and small heterodimer partner (SHP) double knockout mice
unexpectedly exerts anti-obesity and anti-diabetic effects. Intriguingly, liver-specific FXR/SHP ablation
phenocopies the global knockout mice with striking beneficial impacts on white adipose tissue (WAT) fatty acid
utilization and inflammation. This raises the possibility that hepatic BA overload confers metabolic crosstalk
between the liver and adipose tissues. Our preliminary results indicate that hepatic secretion of orosomucoid 2
(ORM2) is dramatically increased by not only BA overload, but also weight-loss Roux-en Y gastric bypass (RYGB)
surgery. Hepatic Orm2 overexpression greatly reduces white adipose tissue (WAT) mass, coupled with marked
improvement in whole-body insulin sensitivity. Importantly, ORM2 dampens proinflammatory interferon-gamma
(IFNγ) and signal transducer and activator of transcription 1 (STAT1) signaling in WAT. These exciting data
support the hypothesis that the hepatokine ORM2 exerts anti-inflammatory effects in WAT, which improves
insulin sensitivity. The goal of this proposal is to critically test our hypothesis by challenging mouse models of
ORM2 expression with various metabolic interventions. In Aim 1, we will determine the metabolic impact of
hepatic ORM2 induction on WAT function in mouse models of obesity and type 2 diabetes. Aim 2 will determine
the contribution of ORM2 to the broad beneficial effects of BA overload and RYGB surgery using Orm2-deficient
mice. Lastly, Aim 3 will define anti-inflammatory effects of ORM2 on CCR5-IFNγ-STAT1 axis in WAT. Our studies
will identify the molecular and cellular basis of hepatokine ORM2 function on WAT inflammation, which
coordinately improves metabolic phenotypes. Ultimately, we expect to provide detailed insight into BA-induced
liver-adipose tissue crosstalk with direct therapeutic potential for treating obesity and type 2 diabetes.

Terms: <A(1)-Acid Seromucoid><Ablation><Acceleration><Acid Seromucoid><Adipocytes><Adipose Cell><Adipose tissue><Adult-Onset Diabetes Mellitus><Animal Model><Animal Models and Related Studies><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-diabetic Agents><Anti-diabetic Drugs><Anti-inflammatory><Antiinflammatory Effect><Bile Acids><Biliary><Binding><Body Composition><Body Tissues><Body Weight decreased><C-C CKR-5><C-C CKR-5 Gene><C-C Chemokine Receptor Type 5><C-C Chemokine Receptor Type 5 Gene><CC Chemokine Receptor 5><CC-CKR-5><CC-CKR-5 Gene><CC-CKR5><CCCKR5><CCCKR5 Gene><CCR-5><CCR-5 Gene><CCR5><CCR5 Protein><CCR5 Receptors><CCR5 gene><CD195 Antigen><CD195 Antigen Gene><CHEMR13><CHEMR13 Gene><CKR-5><CKR-5 Gene><CKR5><CKR5 Gene><CKR5 Receptors><CMKBR5><CMKBR5 Gene><Cardiovascular Diseases><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cellular Function><Cellular Physiology><Cellular Process><Certification><Chemokine (C-C Motif) Receptor 5><Chemokine (C-C) Receptor 5><Chemokine (C-C) Receptor 5 Gene><Chemokine Receptor Gene><Cholalic Acids><Cholic Acids><Communication><Coupled><Data><Diabetes Mellitus><Diet><Distal><Dysfunction><Endocrine><Energy Expenditure><Energy Metabolism><Fat Cells><Fatty Acids><Fatty Tissue><Feedback><Functional disorder><Genes><Goals><HIV-1 Fusion Co-Receptor><HIV-1 Fusion Co-Receptor Gene><Hepatic><Hormone secretion><Humulin R><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><Immune><Immune Interferon><Immunes><Inflammation><Inflammatory><Inflammatory Response><Injury to Liver><Insulin><Interferon Gamma><Interferon Type II><Intermediary Metabolism><Intervention><Intervention Strategies><Intracellular Communication and Signaling><KO mice><Ketosis-Resistant Diabetes Mellitus><Knock-out Mice><Knockout Mice><Link><Lipids><Lipocytes><Liver><Mature Lipocyte><Mature fat cell><Maturity-Onset Diabetes Mellitus><Mediator><Metabolic><Metabolic Diseases><Metabolic Disorder><Metabolic Processes><Metabolic stress><Metabolism><Mice><Mice Mammals><Molecular><Molecular Fingerprinting><Molecular Interaction><Molecular Profiling><Murine><Mus><NIDDM><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Novolin R><Nuclear><Null Mouse><Obese Mice><Obesity><Obesity Epidemic><Operative Procedures><Operative Surgical Procedures><Organ><Orosomucoid><Pathway interactions><Peripheral><Phenocopy><Phenotype><Physiopathology><Receptor Protein><Regular Insulin><Regulation><Role><STAT1 protein><Seromucoid><Serum Sialomucin><Signal Transduction><Signal Transduction Systems><Signaling><Slow-Onset Diabetes Mellitus><Stable Diabetes Mellitus><Stat-1 protein><Stat-91 protein><Stat91 protein><Subcellular Process><Surgical><Surgical Interventions><Surgical Procedure><T2 DM><T2D><T2DM><Testing><Therapeutic><Thesaurismosis><Tissues><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><United States><Weight><Weight Loss><Weight Reduction><adipose><adiposity><adult onset diabetes><alpha 1-Acid Glycoprotein><alpha 1-Acid Seromucoid><anti-diabetic><anti-inflammatory effect><bariatric surgery><biological signal transduction><body weight loss><cardiovascular disorder><chemokine receptor><corpulence><diabetes><diets><energy balance><gastric banding><gastric bypass surgery><hepatic body system><hepatic damage><hepatic injury><hepatic organ system><hormonal secretion><implantable gastric stimulation banding><improved><innovate><innovation><innovative><insight><insulin sensitivity><insulin sensitizer><insulin sensitizing drugs><interventional strategy><ketosis resistant diabetes><lFN-Gamma><liver damage><liver injury><maturity onset diabetes><metabolic phenotype><metabolism disorder><metabotype><model of animal><molecular profile><molecular signature><mouse model><murine model><novel><ob/ob mouse><obesity intervention><obesity surgery><obesity therapy><obesity treatment><overexpress><overexpression><pathophysiology><pathway><receptor><response><signal transducer and activator of transcription 1><social role><stomach stapling><surfactant function><surgery><transcription factor Stat91><type 2 DM><type II DM><type two diabetes><weight loss surgery><weights><white adipose tissue><wt-loss><yellow adipose tissue>