Research

Key Words: Obesity, Diabetes, Insulin Resistance, Beta Cell Dysfunction, Inflammation, Metaflammation, Immunometabolism, Hypoxia, Hypoxia-Inducible Factor (HIF)

Graphical Abstracts

I. Mechanisms for how Inflammation (or metaflammation) Is Initiated and Propagates in Obesity: "Hypoxia Hypothesis"

Early during the development of obesity, increased oxygen consumption (combined with decreased capacity to adaptively increase oxygen supply causes adipocyte hypoxia), which initiates adipose tissue inflammation, insulin eesistance, and adipose tissue dysfunction (Lee et al., Cell 157:1339; Seo et al., Nature Metabolism 1:86)

• Early during the development of obesity, intracellular adipocyte oxygen concentration decreases, causing increased adipocyte HIF-1alpha expression.

• In obese adipocytes, increased intracellular fatty acids increase adipocyte oxygen consumption by stimulating ANT2 (a mitochondrial inner membrane protein)-dependent uncoupled mitochondrial respiration, leading to relative hypoxia.

• Increased adipocyte HIF-1alpha stimulates the expression of chemokines and NO production, triggering adipose tissue inflammation and insulin resistance.

• Adipocyte HIF-1alpha increases adipose tissue lactate production to support hepatic glucose production.

• Adipocyte HIF-2alpha counteracts HIF-1alpha and adipocyte HIF-2alpha KO mice show increased body weight and worse glucose tolerance on high fat diet.

During the development of obesity, increased FFAs stimulate ANT2-dependent pro-inflammatory macrophage activation, contributing to the propagation of adipose tissue inflammation (Moon et al., JCI Insight 6:e147033)

• Obesity increases ANT2 expression in adipose tissue macrophages (ATMs).

• ANT2 expression is enriched in recruited, pro-inflammatory activated ATMs which are increased in obesity.

• FFAs released from obese adipocytes stimulate ANT2, leading to proinflammatory ATM activation.

• FFA- or LPS-induced macrophage ANT2 activation induces opending of the mitochondrial permeability transition pore, leading to increased mitochondrial ROS production.

• ANT2-stimulated mitochondrial ROS causes mitochondrial damage and the activation of pro-inflammatory pathways, such as increased HIF-1alpha and NF-kB expression/activation, leading to pro-inflammatory macrophage activation.

II. Mechanisms for How Adipose Tissue Inflammation And Dysfunction Contributes to The Development of Insulin Resistance And Glucose Intolerance

In Obesity, Dysfunctional, Hypoxic Adipocytes Induce Liver Pseudohypoxia, Causing Increased First Pass GLP-1 Inactivation, Leading to Decreased Incretin Effect and Insulin Secretion (Lee et al., Science Advances 5:eaaw4176)

• In obsity, HIF-1alpha expression increases in liver with a moderate decrease in liver interstitial oxyen tension.

• The obesity-induced decrease in liver interstitial oxyen tension is not sufficient to induce hepatocyte HIF-1alpha expression.

• Instead, factors from obese, dysfunctional adipocytes, released into the blood circulation, such as increased FFAs, leptin, or decreased adiponectin, collectively stimulate increaesd HIF-1alpha expression in hepatocytes.

• Hepatocyte HIF-1alpha causes increased hepatic DPP4 expression and sinusoidal flow resistance, causing increased first pass GLP-1 degradation.

• This leads to decreaesd incretin effect and glucose-stimulated insulin secretion in beta cells.

Systemic Inhibition of Prolyl Hydroxylase Domain (PHD) Enzymes Improves Glycemic Control in Obese Insulin Resistance Mice (Riopel et al., Molecular Metabolism 41:101039): In contrast to the effect of HIF-1alpha, postprandial increases in hepatocyte HIF-2alpha enhance hepatocyte insulin sensitivity and suppresse glucagon action.

• In obesity, physiologic induction of liver HIF-2alpha expression is diminished, contributing to decreased insulin sensitivity and increased glucagon action.

• Administration of a pan PHD inhbitor compound improves glycemic control in high fat diet (HFD), obese, and insulin resistant mice.

• This beneficial effects was dependent on hepatocyte HIF-2alpha expression.

• Hepatocyte HIF-2alpha stimulates IRS2 and cAMP-specific PDE expression in mouse and human hepatocytes, leading to increased insulin and decreased glucagon sensitivity.

• High fat diet/obesity suppresses post-prandial (physiologic) increases in heptic HIF-2alpha expression and PHD inhibitor compound treatment can improve glycemic control by derepressing HIF-2alpha-dependent IRS2 and PDE activation in obese liver.

III. Are There Endogenous Compensatory Mechanisms to Overcome Metabolic Stress in Obesity?: Why some obese patients develop metabolic syndrome, while some (relatively minor subjects) maintain metabolic health? What are upside and downside of obesity-induced inflammation?

In Obesity, Metabolic Stress-Induced HIF-2α Preserves Mitochondrial Activity And Glucose Sensing to Support Beta Cell Compensation (Moon et al., Diabetes 71(8):1617-1619): Early during the development of obesity, even with increased metabolic (oxidative) stress, beta cells increase GSIS to compensate increased body insulin needs and maintain relative euglycemia. However, the underlying mechanism for beta cell compensation was not clearly understood.

• HIF-2α is induced by metabolic stress in beta cells.

• HIF-2α stimulates anti-oxidant gene expression and protects from overt oxidative stress, supporting beta cell compensation.

• Depletion of HIF-2α enhances metabolic stress-induced mitochondrial damage and decreased GSIS in Min6 cells.

• Inducible beta cell HIF-2α KO exacerbates mitochondrial dysfunction and decreased GSIS, potentiating glucose intolerance in obese mice.

The Fractalkine(FKN)/CX3CR1 System in Beta Cell Function and Glycemic Control (Lee et al., Cell 153:413; Riopel et al., Journal of Clinical Investigation 128:1458)

• The fractalkine (FKN)/CX3CR1 system represents a novel regulatory mechanism for insulin secretion and β cell function.

• Chronic administration of a long-acting form of FKN, FKN-Fc, can exert durable effects to improve glucose tolerance with increased glucose-stimulated insulin secretion and decreased β cell apoptosis in obese rodent models.

• Chronic FKN-Fc administration also decreases α cell glucagon secretion.

• FKN inhibits ATP-sensitive potassium channel conductance by an ERK-dependent mechanism, which triggered β cell action potential (AP) firing and decreased α cell AP amplitude.

• This results in increased glucose-stimulated insulin secretion and decreased glucagon secretion.

• FKN-Fc also exerts peripheral effects to enhance hepatic insulin sensitivity due to inhibition of glucagon action

Chronic Fractalkine(FKN)-Fc Administration Improve Atherosclerosis in Ldlr KO mice (Riopel et al., Molecular Metabolism 20:89)

• FKN-Fc treatment blocks monocyte adhesion and rolling on the vascular wall.

• Long-acting FKN-Fc administration prevents atherosclerosis in Ldlr KO mice.

• FKN-Fc administration accelerated diet-induced regression of established atherosclerosis in Ldlr KO mice.

FKN (CX3CL1)-Fc Study: In collaboration with Takeda California, Inc, we studied the effect of a long acting form of fractalkine (FKN-Fc) on glycemic control and the development or treatment of atherosclerosis ( both prevention and intervention mode studies). (Riopel et al., Journal of Clinical Investigation 128:1458; Riopel et al., Molecular Metabolism 20:89)

Pan PHD Inhibitor (PHDi) Study: In collaboration with Johnson and Johnson, Inc, we studied the effect of a pan PHD inhibitor (PHDi) treatment on glycemic control. (Riopel and Moon et al., Molecular Metabolism 41:101039)