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Autophagy and Cardiometabolic Diseases: From Molecular Mechanisms to Translational Medicine
Autophagy and Cardiometabolic Diseases: From Molecular Mechanisms to Translational Medicine
Autophagy and Cardiometabolic Diseases: From Molecular Mechanisms to Translational Medicine
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Autophagy and Cardiometabolic Diseases: From Molecular Mechanisms to Translational Medicine

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Autophagy and Cardiometabolic Diseases: From Moleculer Mechanisms to Translational Medicine covers the science of autophagy in relation to cardiometabolic diseases and the future therapeutic potentials of autophagy regulation in these processes. Processes are not described in isolation, but in concert with other cellular and/or metabolic processes, such as lipogenesis, glucose, energy metabolism and apoptosis. This approach recognizes the multifactorial nature of cardiometabolic diseases, including obesity, diabetes, insulin resistance, hypertension and dyslipidemia. The book provides explanations, while also distinguishing the delicate role for autophagy in pathogenesis and exploring complications for cardiometabolic diseases.

By targeting autophagy, it offers new avenues for drug discovery and treatment for cardiometabolic anomalies. It is a perfect resource for cardiology researchers, scientists and medical practitioners.

  • Explains the processes inherent in the protein quality control for pathogenesis and complications of cardiometabolic diseases
  • Provides knowledge from internationally recognized contributors in the field
  • Incorporates a translational approach, covering the basic cellular biology of autophagy and presenting the role of autophagy regulation for both pathogenesis and complication in cardiometabolic diseases
  • Contains access to a companion website with additional illustrations
LanguageEnglish
Release dateApr 12, 2018
ISBN9780128054420
Autophagy and Cardiometabolic Diseases: From Molecular Mechanisms to Translational Medicine
Author

Jun Ren

Dr. Jun Ren, MD, PhD, FAHA, is a Professor and Associate Director in University of Wyoming Biomedical PhD Graduate Program. He is also an Adjunct Professor of Cardiology in the Department of Cardiology, Zhongshan Hospital Fudan University. He is a member of American Heart Association and Diabetes Association National Center Study Sections. Dr. Ren specializes in the molecular cardiology with the goal that is to develop a strategy to prevent cardiovascular and a better regimen of treating these disorders. Serving as PI on several federal or national grants, he has completed enormous researches arming him with experience in cardiac function and structure assessment. In addition, he successfully administered the projects (e.g. staffing, research protections, budget), supervised students, and collaborated with other researchers. He has published over 500 articles with a main research interests in Cardiovascular and neurodegenerative diseases.

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    Autophagy and Cardiometabolic Diseases - Jun Ren

    strategies.

    Section I

    Cell Biology of Cardiometabolic Syndrome and Autophagy

    Chapter 1

    Overview of Autophagy and Cardiometabolic Syndrome

    Annayya R. Aroor⁎,†; Guanghong Jia⁎,†; James R. Sowers⁎,†,‡    ⁎ University of Missouri-Columbia School of Medicine, Columbia, MO, United States

    † Harry S. Truman Memorial Veterans Hospital, Columbia, MO, United States

    ‡ Dalton Cardiovascular Center, University of Missouri, Columbia, MO, United States

    Abstract

    The term cardiometabolic syndrome (CMS) refers to a constellation of cardiac metabolic and cardiovascular disease (CVD) risk factors including overweight/obesity, insulin resistance/hyperinsulinemia, hypertension, metabolic dyslipidemia, and microalbuminuria. Obesity is a central component of the CMS that is driven by consumption of high fat/refined carbohydrate diet and a sedentary lifestyle. Persons with the CMS have an increased risk for the development of type 2 diabetes mellitus, CVD, and chronic kidney disease. This increased risk is related to endothelial dysfunction, increased cardiovascular stiffness, impaired vascular and cardiac diastolic relaxation, and kidney disease. A pivotal component of CMS is systemic and tissue insulin resistance and one important link between insulin resistance and progression of CMS is autophagy. Autophagy is essential for effective maintenance of intracellular metabolic homeostasis and tissue quality control. However, this pathway is dysregulated in CMS and characterized by either inefficient autophagy or exaggerated/maladaptive autophagy and related to the development of insulin resistance. Both autophagy and insulin metabolic signaling are altered in CMS through interactions of excess dietary nutrients and inappropriate activation of renin-angiotensin-aldosterone system and inflammation. This overview addresses new insights into the interaction between abnormal autophagy and insulin resistance in the genesis and progression of the CMS, as well as potential strategies for drug targeting and lifestyle interventions to prevent and/or correct maladaptive autophagy and improve insulin sensitivity.

    Keywords

    Autophagy; Cardiometabolic syndrome; Insulin resistance; Obesity; Quality control; Diabetes

    Acknowledgments

    This work was supported by Grants from the National Institutes of Health (HL-073101 and HL-107910 to J.R.S.) and the Department of Veterans Affairs Biomedical Laboratory Research and Development (BX001981 to J.R.S.). The authors would like to thank Brenda Hunter for her editorial assistance and Brady Barron for supervising the research conducted in our laboratory.

    Disclosure: The authors have nothing to disclose.

    1.1 Introduction

    The term cardiometabolic syndrome (CMS) refers to a constellation of interactive metabolic and cardiovascular disease (CVD) risk factors including overweight/obesity, hypertension, insulin resistance/hyperinsulinemia, metabolic dyslipidemia, and microalbuminuria (Fig. 1.1) [1–6]. According to the National Cholesterol Education Program Adult Treatment Panel III, the criteria for the diagnosis of CMS are based on any three of these abnormalities [2,5]. The incidence of CMS has been reported to be approximately 35% of the adult population and 50% in those older than 60 years of age in the United States, with a significantly higher incidence in women (35.65%) compared to men (30.3%) [5]. There is substantial evidence that overweight/obesity is the driving force for the development of CMS [2,7]. Lack of physical activity and consumption of a western diet (WD) rich in saturated fat/refined carbohydrates such as fructose are the major factors that contribute to overweight/obesity and development of CMS [3,7]. Indeed, the consumption of high-fructose corn syrup has increased dramatically in the past three decades in the United States [3,7–9]. Development of the CMS is also dependent on the interaction of sedentary lifestyle and a WD with genetic, epigenetic, and other environmental factors such as air pollution [7].

    Fig. 1.1 Overview of cardiometabolic syndrome.

    1.2 Epidemiology and Pathophysiology

    Two-thirds of American adults are overweight or obese, 75 million are hypertensive, and over 30 million are diabetic [2,10]. Moreover, the incidence of type 2 diabetes mellitus (T2DM) has increased by 40% in the United States during the last few decades [11]. Depending on the criteria used for definition of CMS, region, composition of the population, the global prevalence of CMS is in the range of 10%–84% [12–14]. The health burden of overweight/obesity is also increasing worldwide with excess body weight estimated to account for more than four million deaths [15]. The presence of these risk factors also confers a substantial increase in the risk for CVD including heart failure, coronary heart disease, stroke, and all-cause mortality [1,2,10,16–18]. The risk for the development of stroke is estimated to be increased two- to fourfold and myocardial infarction is estimated to be three- to fourfold whereas mortality from cardiovascular events is increased to twofold with the presence of CMS [17,19–21]. The risk for the development of CVD increases more frequently with the number of components of CMS [22,23]. In addition to the association with future development of T2DM and CVD, the CMS is closely associated with development of albuminuria and chronic kidney disease (CKD) [2,10,24,25]. Moreover, nonalcoholic fatty liver disease (NAFLD) is increasingly recognized in association with CMS [25–27]. Recent studies demonstrating endothelial dysfunction in association with the development of NAFLD [26,27] emphasize the impact of CMS on the parallel progression of NAFLD and CVD in the setting of obesity, especially visceral obesity (Fig. 1.1).

    1.2.1 Obesity

    The epidemic obesity is driven by lack of physical activity and increased consumption of diet rich in fat and refined carbohydrates which in turn is further modified by genetic and environmental factors [7,15]. Adipose tissue is comprised of adipocytes, preadipocytes, endothelial cells, and immune cells. Although both subcutaneous and visceral adipose tissue are implicated in obesity, visceral adiposity largely contributes to the development of CMS [28]. In recent years the role of brown adipose tissues, white adipose tissues, and beiging of adipose tissues in the development of immune and inflammatory response and adipocyte remodeling have been reported [29]. Hypertrophic and hyperplasic response coupled to adipocyte stiffness in response to over nutrition accounts for altered metabolic and immune responses in obesity [3,30]. An additional factor that contributes to adipocyte dysfunction is hypoxia resulting from adipocyte expansion [13]. The prorogation of maladaptive immune and inflammatory response, release of fatty acids and adipocytokines mount hepatic steatosis, dyslipidemia, and cardiovascular dysfunction and kidney disease [15,31]. In addition to visceral adiposity, recent studies have implicated adipose tissue dysfunction surrounding vascular, heart, and kidney in the pathogenesis of CVD and CKD [15,32].

    1.2.2 Insulin Resistance and Progression of CMS

    Diminished systemic and CV insulin sensitivity is a common feature in obesity, hypertension, and diabetes contributing to the progression of CVD and CKD [6,33] (Fig. 1.1). The significance of cardiovascular insulin resistance is underscored by the early occurrence of CV insulin resistance compared to systemic insulin resistance [3]. CV tissue insulin resistance in CMS is associated with decreased bioavailable nitric oxide (NO), arterial stiffness, and cardiac diastolic dysfunction in the absence of coronary heart disease and hypertension [34,35]. Arterial stiffness often precedes the development of hypertension, atherosclerosis, coronary artery disease, heart failure, and stroke [35]. Moreover, insulin resistance may precede, facilitate, and predict microalbuminuria which is a well-established early risk marker for vascular endothelial dysfunction and associated glomerular and tubular dysfunction [9] and renal insulin resistance associated with obesity contributes to the progression of CKD [36].

    1.2.2.1 Impairment of Metabolic Insulin Signaling in CMS

    Insulin signaling occurs mainly through two signaling components: metabolic signaling pathway and growth factor signaling pathway [35,37]. Metabolic signaling pathway occurs through activation of the phosphatidylinositol 3 kinase (P13K)/protein kinase B(Akt) signaling pathway. Activation of Akt causes phosphorylation of endothelial nitric oxide synthase (eNOS) at ser 1177, regulates FOXO transcriptional factor signaling, expression of heme oxygenase, and phosphorylation of AS160 and glucose uptake by the insulin-sensitive tissues thereby regulating influx of metabolic substrates and substrate metabolism in both mitochondria and extra mitochondrial cellular compartment [37]. NO availability is essential for several functions of endothelium as well as other cellular components of the vasculature including vascular stiffness, vascular relaxation, permeability, cell proliferation, control of immune/inflammatory response, and regulation of cardiac and vascular fibrosis [6]. Bioavailability of endothelial NO depends on NO production by efficient arginine transport, and eNOs activation and availability of cofactors but also by its destruction by oxidative stress [38,39].

    1.2.2.2 Insulin Regulation of Growth Factor Signaling Pathway

    The second pathway insulin signaling is growth factor signaling pathway in which activation of ERK1/2 occurs with growth factor-like responses including increased production of vasoconstrictor endothelin 1(ET-1) [6,39].

    1.2.2.3 Insulin Receptor Substrate-1 and Pathway Selective Insulin Resistance

    The major converging point of this pathway is the docking protein insulin receptor substrate-1/2 [35,39]. In the setting of insulin resistance the phosphorylation of serine residues of IRS by several kinases including protein kinase C, p70S6 kinase 1, rho kinase, ERK1/2, c-jun kinase (JNK1/2), mTOR1 is the major mechanism of inhibition of IRS-1 signaling [35,39]. Regulation of IRS1 protein levels by proteasome-dependent degradation of IRS-1 when IRS-1 is phosphorylated on specific serine residues also results in decreased IRS1-mediated insulin signaling [35]. Under this setting the metabolic signaling gets impaired but growth factor signaling occurring in IRS-1-independent pathway is not affected or enhanced [39]. This pathway selective impairment/imbalance in insulin signaling leads to suppression of insulin metabolic signaling but enhancement of growth factor signaling including increased expression of endothelin-1 that also contributes to CV dysfunction in CMS [39,40].

    1.2.2.4 Inappropriate Activation of RAAS, Cytokine Imbalance, High-Fructose Diet, Oxidative Stress, and Insulin Resistance

    The enhanced cytokine response also leads to activation of serine kinases that phosphorylate IRS-1 which results in further impairment in insulin metabolic signaling [40,41]. In this regard, TNF-mediated activation of NF-KB signaling causes activation of mTOR signaling and S6 kinase activation [3]. Decreased bioavailable NO may also occur through increased destruction of NO by reactive oxygen species (ROS) which in turn caused by activation of NADPH oxidases, xanthine oxidase, and mitochondrial production of ROS [35]. Activation of macrophage NADPH oxidase is also an important source of ROS in addition to ROS production by endothelial NADPH oxidases [7,42,43]. Inappropriate activation of systemic and tissue renin-angiotensin II-aldosterone system (RAAS) is recognized as a major factor in determining insulin resistance and vascular dysfunction. Indeed, in addition to conventional activation of systemic RAAS, presence of RAAS components has been detected in tissues such as heart, vasculature, adipose tissue, immune cells, and brain [44]. The increased production of RAAS in the vasculature by high glucose and insulin suggests local vascular RAAS activation contributes significantly to progression of vascular dysfunction in CMD [41,44,45]. The molecular mechanisms of RAAS-mediated vascular insulin resistance are not well understood. Recent studies have shown the role of cytokine imbalance caused by maladaptive immune and inflammatory response in relation to inappropriate activation of RAAS as one of the determinants of tissue and systemic insulin resistance and progression of CMS [6,46,47]. We have shown previously Ang II inhibition of insulin metabolic signaling in endothelial cells through Ang II-mediated activation of mTOR/S6 kinase 1 [48]. Recently we have shown suppression of vascular insulin resistance, impaired vascular relaxation and endothelial stiffness, and immune inflammatory response by MR antagonism in obese WD-fed female mice using low-dose spironolactone and endothelial cell mineralocorticoid receptor KO mice fed western diet [49–52]. Activation of xanthine oxidase and increased production of uric acid in both liver and extrahepatic tissues including vasculature caused by consumption of fructose-rich diets and drinks are associated with increased oxidative stress, inflammasome response, and insulin resistance [9,53]. Serum uric acid levels are frequently elevated in individuals with obesity, hypertension, cardiovascular, and kidney disease [54,55]. Therefore hyperuricemia is increasingly recognized as a significant contributing factor for the progression of cardiac and renal complication of CMS.

    1.2.3 Dyslipidemia

    Lipid abnormalities in CMS are associated with increase in LDL-cholesterol and decrease in HDL-cholesterol, increase in plasma triglycerides and increase in levels of oxidized LDL-cholesterol, and increase in plasma-free fatty acids [13,56]. Increase in oxidized cholesterol and free fatty acids contributes to the development of endothelial dysfunction and CV insulin resistance [13,57]. Alteration in composition and function of LDL and HDL further contributes to cardiovascular remodeling, vascular inflammatory response, development of CV, and renal complications associated with CMS [56,58].

    1.2.4 Cardiovascular Disease

    Hypertension is more common in CMS with other metabolic components of CMS than in the general population [7,59]. The health burden of hypertension is highlighted by the occurrence of prehypertension state in 37% of the adult US population and 40% of these people will progress to hypertension within 2 years of diagnosis of prehypertension state [59,60]. CV insulin resistance, endothelial dysfunction, and arterial stiffness are the early vascular manifestations of CMS [33,61,62]. Arterial stiffness is considered to be an independent risk factor for the progression of CVD and CKD during the progression of CMS [10,63,64]. Although hypertension as one of the component of CMS is considered to be an important factor for the contribution of arterial stiffness, development of arterial stiffness in prehypertensive subjects [45,59] and occurrence of arterial stiffness before the development of hypertension in both male and female mice fed high fat/high refined carbohydrates suggest arterial stiffness associated with insulin resistance; endothelial dysfunction suggests arterial stiffening is a significant contributor to the development of hypertension in CMS [7,45].

    Heart failure (HF) is more frequently associated with development of CVD in CMS [2,6,35,65]. More than 5 million people in the United States have HF and cost of annual health burden exceeds 40 billion dollars [2]. HF with preserved ejection fraction is the most common form of HF seen in these patients with both aging and overnutrition as the most significant contributing factors [2,59]. The importance of metabolic insulin signaling in myocardial function has been demonstrated using isolated perfused heart preparations, cultured cardiomyocytes, and positron tomography (PET) in human and animal hearts [35]. Furthermore, development of cardiac insulin resistance occurring earlier than onset of insulin resistance in skeletal muscle has been demonstrated in the hearts of C57BL/6 mice [3,35]. We have shown the role of activation of RAAS in genetic models of obesity using Ren2 transgenic rats and Zucker obese rats [33,66]. In these models antagonism of Ang II signaling and MR signaling results in improvement of metabolic insulin signaling and diastolic dysfunction. Our recent studies also show the role of MR activation in the promotion of cardiac insulin resistance and cardiac fibrosis and diastolic dysfunction [49,52].

    1.2.5 Kidney Disease

    There is accumulating evidence that overweight/obesity is associated with increased risk for the development of CKD [2,9]. The rate of end-stage renal disease increased in a fashion proportional to body mass index in a follow-up study for 10–35 years in large cohort study of 320,252 adults [67]. The odds ratio for developing CKD in CMS patients compared to without CMS was 1.43 as revealed by Atherosclerosis Risk in Community study [68]. The odds ratios for microalbuminuria and CKD were 1.89 and 2.60 when the association of components of conventional CMS syndrome with the risk for both microalbuminuria and CKD was examined [69] for evaluation in the Third National Health and Nutrition Examination Survey (NHANESIII). The risk for progression of CKD in CMS is proportional to the number of individual components of CMS [2]. Childhood obesity is also associated with development of microalbuminuria in men younger than 60 years of age [59,70]. The incidence of end-stage renal disease is increased with rising BMI and the CMS after adjusting for age, systolic blood pressure, and proteinuria [71].

    1.3 Physiological Role of Autophagy: Cellular Control of Metabolism and Regulation of Tissue Quality Control

    One common link between obesity and the development of insulin resistance appears to be inappropriate regulation of autophagy which is either inefficient or exaggerated but maladaptive and defective (Figs. 1.2 and 1.3) [72–78]. Autophagy affords a mechanism by which nutrient utilization is balanced and cellular quality control is regulated. Maladaptive autophagy responses in the CMS may be caused by overweight/obesity and associated insulin resistance and lead to further progression of insulin resistance thus causing a feed-forward loop in the development and progression of the CMS [74,78,79]. The role of excessive nutrient intake in increased mammalian target of rapamycin (mTOR) signaling relative to adenosine monophosphate-activated protein kinase (AMPK) signaling in promotion of dysregulation of autophagy and metabolic low-grade immune inflammatory responses (metainflammation) is increasingly recognized [80] (Fig. 1.2). In this overview we provide a contemporary understanding of the CMS in relation to molecular mechanisms of autophagy and insulin resistance. Strategies for drug targeting to prevent and treat inefficient and maladaptive autophagy and improve systemic and tissue insulin sensitivity in CMS are also considered.

    Fig. 1.2 Overnutrition, autophagy, insulin resistance, and cardiometabolic syndrome. Interactions of overnutrition and inappropriate action of RAAS result in enhanced oxidative stress and maladaptive immune/inflammatory response. The development of maladaptive autophagy and insulin resistance, and the cross talk between the signaling pathways lead to impairment of cytoprotective and quality control role of autophagy (shown in blue boxes ) and impairment of metabolic insulin signaling. This results in the development of constellation of features of cardiometabolic syndrome

    Fig. 1.3 Regulation of autophagy, cross talk between insulin signaling and autophagy, and drug targeting components of autophagy. Dysregulation of autophagy and associated insulin resistance leads to a forward response of oxidative stress and immune/inflammatory response with the development of endoplasmic reticular stress and mitochondrial dysfunction. Drug targeting RAAS activation, mTOR1 signaling, stimulation of AMPK signaling, and lifestyle intervention of exercise are promising approaches for preventing/treating impaired/maladaptive autophagy and insulin resistance in cardiometabolic syndrome.

    1.3.1 Types of Autophagy

    Autophagy is an intracellular catabolic process which enables cells to degrade unwanted cellular components within a double membranous structure formed upon fusion with the lysosome. The products released during autophagy are simple carbohydrates, amino acids, nucleosides, free fatty acids (FFA), and heme-derived substances which are utilized for other cellular processes. Therefore autophagy is considered as a cellular process regulating quality control and regeneration while facilitating the adaptive metabolic changes and integrating catabolic and anabolic pathways [72–74,80]. Autophagy can also be a stress response mechanism that is maladaptive and occurs during cellular adaptation in pathophysiological states such as in obesity, CMS, and diabetes [78,81,82]. There are three main types of autophagy that differ in their mechanism of delivering their cargo to the lysosome: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA) [83]. The best characterized autophagy is macroautophagy, which is often simply termed autophagy. Different types of macro-autophagy include aggrephagy, characterized by clearance of misfolded proteins; lipophagy for clearing lipid droplets; glycophagy for clearing carbohydrates, ferritinophagy for clearing iron; mitophagy for clearance of dysfunctional mitochondria; ribophagy for clearing ribosomes; and peroxophagy for clearing peroxisomes [72,83]. Microphagy refers to invagination of lysosomal membranes through which cytosolic components are taken up and degraded. CMA is a type of autophagy in which targeted proteins are bound to chaperone proteins such as heat shock protein 70 (hsc70), which are directed to the lysosomes where degradation occurs [72,80].

    1.3.2 Process of Autophagy

    The process of autophagy includes initiation, nucleation, elongation/maturation, fusion with lysosome, and degradation of cargo (Fig. 1.3). In mammals, there are multiple autophagy-related (Atg) homologs found in yeast as well proteins that do not have a yeast counterpart [80,82,84].

    1.3.2.1 Induction

    The induction of autophagy is initiated by activation of UNC-51-like kinase 1(ULK1). In nutrient-rich conditions the ULK1 complex is phosphorylated/inactivated by the mTOR1 complex. Under starvation conditions the mTOR1 complex is dissociated from the ULK1 complex and ULK1 is dephosphorylated [72]. ULK1 complex becomes active and phosphorylates Atg 13 and 200 kDA FAK-interrelated protein (FIP200) and the autophagic process.

    1.3.2.2 Nucleation

    The nucleation process is initiated by recruitment of the Beclin-1-vsp34 complex to site of autophagosome formation through phosphorylation of Ambra1 and Beclin-1 by the activated ULK1 complex. Activation of vsp34 complex results in the generation of phopshatidylinsositiol-3-phosphate (PIP3). PIP3 recruits additional proteins to promote autophagosome formation.

    1.3.2.3 Vesicle Elongation and Maturation

    The vesicle elongation process is mediated by two ubiquitin-like conjugated ATG protein complexes: ATG12-ATG5-ATG16L and ATG8 (LC3)-phosphatidylethanolamine (ATG8/LC3-PE). The interaction of these two systems results in the generation of LC3-PE. LC3-PE is localized to the autophagosome membrane and facilitates the expansion of autophagy vesicles.

    1.3.2.4 Fusion With Lysosome and Degradation

    The fusion with lysosomes and resultant formation of autophagolysosomes is facilitated by the interaction of p62 (an autophagy receptor) and other proteins depending on the type of selective autophagy involved in binding of ubiquitinated proteins for proteolytic degradation [75,76]. P62 is a multifunction protein comprising several interacting domains including N-terminal phox-BEM1 domain (PBI), LC-interacting region (LIR), a keap1-interacting domain (KIR), and a c-terminal ubiquitin-associated domain (UBA) [85]. These domains are involved in the interaction of p62 with ubiquitin for delivering polyubiquitinate proteins to the proteasome, thereby providing a link between autophagy pathway and ubiquitin-proteasome system upon ubiquitinated protein degradation [85,86]. The regulation of p62 level in the cell occurs though transcriptional control by oxidative stress and mitogen-activated protein kinase pathway [87]. It is also induced by proteasome inhibition and starvation [88]. It is also regulated by autophagy since it is one of the substrate in the autophagy degradation process [85,86].

    1.3.2.5 Termination of Autophagy

    This process is usually achieved through reactivation of the mTOR complex by nutrient-rich conditions. Reactivation of the mTOR1 complex also results in the formation of protolysosomal vesicles that are extruded from autolysosomes and mature into functional lysosomes [77,78,89].

    1.4 Molecular Regulation of Autophagy: Cross Talk Between Insulin Signaling and Autophagy

    Autophagy is tightly regulated by posttranscriptional signaling mechanisms involving mTOR1; AMPK; sirtuins; antiautophagy protein (Bcl-2); and transcriptional regulation by factors such as peroxisome proliferator-activated receptor alpha (PPARα), cAMP response element binding protein (CREB), basic helix-loop-helix transcription factor EB (TFEB), and FoxO and farnesoid X receptor (FXR). FXR is a negative regulator of autophagy whereas other transcription factors are inducers of the autophagy machinery [90,91]. However, these transcription factors are further regulated by signaling cascades such as FoxO3 [90,92].

    1.4.1 Insulin Regulation of Autophagy Through Both Metabolic and Growth Factor Signaling

    Insulin signaling occurs through both a metabolic and a growth factor pathway [10,35]. The metabolic signaling pathway precedes through activation of the P13K/Akt cascade. Activation of Akt causes phosphorylation of eNOS at Ser 1177, regulates FOXO transcriptional factor signaling, expression of heme oxygenase, and phosphorylation of AS160 and glucose uptake. Further, insulin signaling regulates influx of metabolic substrates and substrate metabolism in both mitochondria and extra mitochondrial cellular compartment [35,39]. Insulin signaling-associated increases in NO are essential for normal CV relaxation, and reduction in insulin signaling and NO promotes increased inflammation and fibrosis [41,93,94]. An important regulator of autophagy, mTOR signaling is also regulated by insulin metabolic signaling [3,10]. Indeed, mTOR is a part of two multiprotein complexes: mTORC1 and mTORC2. The downstream substrates of mTOR1 include S6 kinase 1 (S6K1), 4E-BP1, eIF-2 kinase, and eEF2 kinase where in regulation of latter two kinases are indirect through regulation of upstream kinases [34].

    1.5 Dysregulation of Autophagy and Associated Insulin Resistance

    1.5.1 Nutritional Regulation of mTOR1-AMPK-Sirtuin Signaling Pathway

    1.5.1.1 mTOR1 Signaling

    Activation of mTOR1 is associated with suppression of autophagy as demonstrated in several rodent models of obesity, CMS, and diabetes [80]. Multiple mechanisms account for the activation of mTOR1 in overnutrition and obesity. In addition to insulin signaling, the mTOR1 signaling pathway is also stimulated by branched chain amino acids [95,96]. This pathway occurs independent of TSC1/2 signaling and involves Rag GTPases [94] (Fig. 1.3). mTOR1 activation inhibits autophagy through phosphorylation of ULK1 thereby causing dissociation of the ULK1 active complex, inhibition of lipid kinase activity of VPS34, and downregulation of Atg7 [97,98].

    1.5.1.2 AMPK Regulation of mTOR Pathway and Autophagy

    The mTOR1 pathway is also regulated by AMPK which plays an important role in stimulation of autophagy [99]. AMPK is ubiquitously expressed and activated when the cellular energy generation is low. Under condition of starvation, the levels of AMP are increased which results in activation of AMPK. This, in turn, inhibits mTOR1 by AMPK-mediated phosphorylation of TSC2 as well as phosphorylation and inactivation of RAPTOR [10,99]. Stimulation of autophagy by AMPK is also accompanied by other effects of AMPK: suppression of global protein synthesis, mitochondrial biogenesis, and induction of eNOS activation [100,101]. AMPK also promotes autophagy by mTOR1-independent mechanisms through phosphorylation of ULK1 [94,101].

    1.5.1.3 Sirtuins

    Although silent information regulator proteins (sirtuins) are usually classified as class III histone deacetylases, they catalyze deacetylation of histones as well as nonhistone proteins. SIRT1 is the major sirtuin that modulates autophagy and its levels are decreased in CMS [80]. It is an NAD+-dependent protein deacetylase that positively regulates autophagy. It also serves as a nutrient-sensing pathway. SIRT1 deacetylates essential components of autophagy such as ATG5, ATG7, and LC3. SIRT1 also deacetylates transcription factor FOXO3 which in turn promotes autophagy [102]. SIRT1-induced deacetylation of FOXO1 also results in stimulation of autophagosome formation [103].

    1.5.2 Inappropriate Activation of Renin-Angiotensin-Aldosterone System (RAAS) and Oxidative Stress

    Enhanced activation of systemic and tissue RAAS is recognized as a major factor in promoting insulin resistance and CV dysfunction [61]. However, in addition to conventional activation of systemic RAAS, presence of RAAS components has been detected in tissues such as heart, vasculature, and adipose tissue. The molecular mechanisms of RAAS-mediated CV insulin resistance are not well understood. Enhanced oxidative stress due to activation of NADPH oxidases, xanthine oxidase, and mitochondrial dysfunction may contribute to oxidative stress-mediated activation of redox-sensitive kinases causing impaired insulin metabolic signaling and associated impaired/maladaptive autophagy [35,48,50,104,105]. These observations underscore the importance of targeting the RAAS to induce a protective autophagy response.

    1.5.3 Maladaptive Immune and Low-Grade Inflammatory Response Leading to Cytokine Imbalance, Insulin Resistance, and Dysregulated Autophagy

    Insulin resistance in obesity and diabetes is promoted by a low-grade inflammatory response [3] which is associated with a proinflammatory polarization of macrophages and lymphocytes which promote increased secretion of cytokines such as tumor necrosis factor alpha (TNFα) and interleukin (IL)-6. In turn, this results in further impairment of insulin metabolic signaling [38] (Fig. 1.1). Recent studies have also demonstrated a possible role for macrophage-mediated oxidative stress in inhibition of autophagy [106]. To this point, deletion of macrophage-specific Atg7 results in an increased proportion of M1 proinflammatory macrophages and enhanced reactive oxygen species (ROS) accumulation [107]. Further, mitochondrial dysfunction results in mitochondrial ROS accumulation which, in turn, activates the nucleotide-binding domain, leucine-rich containing family, pyd domain containing-3 (NLRP-3) inflammasome response which promotes insulin resistance and impaired autophagy [108,109] (Fig. 1.2).

    1.5.4 Endoplasmic Reticular (ER) Stress

    The ER is essential for protein synthesis as well as the maturation process that involves proper folding and assembly of proteins [110–112]. ER stress is an unfolded protein response stimulated by accumulation of misfolded proteins that is associated with induction of autophagy aimed to reduce cellular stress. However, excessive ER stress may result in dysfunctional autophagy and insulin resistance [34,110]. ER stress also increases the production of mitochondrial oxidative stress, which in turn has a negative impact on autophagy and insulin metabolic signaling [113] (Fig. 1.2).

    1.6 Dysregulation of Autophagy and Progression of CMS

    1.6.1 Adipose Tissue Dysfunction (Figs. 1.1 and 1.2)

    Obesity, especially expansion of visceral white adipose tissue, results in increased secretion of proinflammatory adipokines such as angiotensinogen, aldosterone, dipeptidylpeptidase 4 (DPP-4), leptin, resistin, TNFα, and IL-6 [3,30]. Moreover, greater lipolytic activity in visceral adipose tissue leads to an increase in FFAs. FFAs inhibit insulin-stimulated glucose uptake and metabolic insulin signaling in adipose as well as nonadipose tissues [35]. Moreover, increased FFA in the portal vein results in an increased influx of fatty acids to the liver resulting in increased hepatic synthesis of diacylglycerols and triglycerides, which in turn result in hepatic insulin resistance, hyperglycemia, and hyperinsulinemia [27].

    Autophagy plays a role in adipose tissue differentiation/expansion and its metabolic regulation [114]. Targeted deletion of Atg5 and Atg7 impairs adipogenesis, especially of white adipose tissue [115,116]. Deletion of Atg7 in murine adipose tissue results in mice that are resistant to obesity when fed with high-fat diet [117]. In obese and diabetic patients there is increased autophagic flux and increases in autophagosome content in isolated adipocytes [118,119]. In T2DM patients, impaired activation of mTOR1, secondary to insulin resistance, may partly account for enhanced autophagy [42]. Further, there are increases in adipose tissue autophagy in mouse model of diet-induced obesity which is reversed upon calorie restriction suggesting altered regulation of autophagy under the setting of obesity [114,120,121].

    1.6.2 Vascular Dysfunction (Fig. 1.2)

    Endothelial dysfunction and arterial stiffness are the early vascular manifestations of cardiometabolic disease [61]. Arterial stiffness is considered to be an independent risk factor for the progression of CVD and CKD [40,63,122–124]. Emerging evidence suggests that endothelial dysfunction is caused, in part, by impaired autophagy [89,125–130]. Impairment of endothelial autophagy results in increased shear stress-induced oxidative stress and increased production of inflammatory cytokines [130]. Moreover, stimulation of autophagy by activation of AMPK offers protection against oxidant-induced cell death of endothelial cells (ECs). Recent studies of isolated ECs from diabetic patients demonstrated impairment of autophagy flux in ECs and associated reductions in bioavailable NO [131,132]. Aging accelerates vascular dysfunction and stiffness in states of obesity and the CMS [61]. In this regard, expression of autophagy is decreased in ECs from aged humans and mice. This impaired autophagy is associated with a decrease in bioavailable NO and impaired endothelial-dependent arterial dilatation. Moreover, treatment of aged mice with autophagy enhancers corrected impaired autophagy and associated vascular abnormalities [131].

    1.6.3 Cardiac Dysfunction (Fig. 1.2)

    Autophagy in cardiomyocytes [1] meets metabolic needs during ischemia reperfusion, [2] mediates cardiomyocyte remodeling during pressure overload, and [3] modulates cardiac remodeling in heart failure associated with hypertension and ischemic heart disease [126,133–135]. Recent studies have demonstrated a key role of altered autophagy associated with insulin resistance in cardiac dysfunction in obesity and CMS [78,79,105,136]. Inappropriate activation of the RAAS in nutritional and genetic models of obesity is associated with cardiac insulin resistance, altered autophagy, and diastolic dysfunction [7,33,49,52,79]. The cross talk between CV insulin resistance and autophagy is supported by impairment of cardiac autophagy in rodent models of CV insulin resistance, CMS, and T2DM. Indeed, impairment in autophagy maturation or autophagy flux has been reported in rodent models of diet-induced obesity [77–79]. Enhanced initiation of autophagy but impairment of autophagic flux has also been seen in cardiac tissue from insulin-resistant mice [136]. Normal induction of autophagy promotes increased degradation of collagen type 1 which could accumulate as aggregates in the endoplasmic reticulum in fibroblasts [126,137]. In this regard, deletion of beclin-1 in kidneys results in increased accumulation of collagen [138] but the effects of fibroblast-specific autophagy deficiency on cardiac fibrosis have not been examined.

    1.6.4 Kidney Disease

    The role of impaired autophagy in the pathophysiology of kidney disease is not well understood. However, autophagy has been evaluated in podocytes and proximal renal tubule cells [100]. Podocytes are major players in maintaining the filtration barrier and podocyte injury is one of the factors contributing to albuminuria which is increasingly recognized as an integral component of the CMS [100]. Podocytes normally exhibit high autophagy activity that is associated with decreased mTOR1 signaling [100]. Impaired podocyte autophagy has been observed in kidneys from high-fat diet-fed rodents, genetic models of obesity, and rodent models of diabetic nephropathy [100,139]. Podocyte-specific deficiency in Atg5 in aged mice increases ER stress and the accumulation of oxidized and ubiquitinated proteins/organelles and glomerular damage [140]. Moreover, insufficient podocyte autophagy has been demonstrated in patients with diabetes and massive proteinuria [100]. In addition, the role of endothelial autophagy in limiting the progression of diabetic nephropathy has also been reported [45]. Mice with proximal tubular-specific deletion of Atg5 develop severe proteinuria suggesting a protective role of autophagy in proximal renal tubular cells. Further, renal autophagy activity is decreased in obese mice, and this reduced autophagy is associated with the accumulation of damaged molecules such as p62 and mitochondria suggesting impaired autophagy flux. Proximal tubular cells of obese T2DM patients also show accumulation of p62 protein [141,142].

    1.6.5 Pancreatic β Cell Dysfunction

    Autophagy helps to maintain normal beta cell mass and function [73,143]. Dysregulation of beta cell autophagy has been demonstrated in obese diabetic rodents [144] and T2DM patients [145]. Deletion of the beta cell-specific key autophagy regulatory protein Atg7 results in a decrease in beta cell mass, lowered insulin content, hypoinsulinemia, and hyperglycemia [146]. Similarly, autophagy-deficient beta cells show defects in a compensatory increase in beta cells in high-fat diet-fed mice [147]. Moreover, improved beta cell function and concomitant reduction in ER stress have been accomplished by stimulation of autophagy [148].

    1.7 Drug Targeting for Insulin Resistance and Autophagy in CMS

    Drugs that target single or multiple components of autophagy represent potential therapeutic strategies to prevent and treat various components of the CMS [75,76,89] (Fig. 1.3). Such targets include mTOR1, AMPK, and SIRT1 which are key nutrient signaling molecules that modulate both autophagy and insulin metabolic signaling. Stimulation of AMPK and SIRT1 signaling and inhibition of mTOR1 signaling could result in both improvement in stimulation of autophagy and improve insulin metabolic signaling [76,89,149–152]. Since upregulation and maladaptive autophagy are seen under the setting of upregulation of RAAS, suppression of inappropriate activation of RAAS by angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers (ARBs), or mineralocorticoid receptor antagonists, could potentially ameliorate maladaptive autophagy and improve insulin sensitivity. In this regard, altered myocardial autophagy and enhanced mitochondrial degradation, along with left ventricular hypertrophy were corrected with ARB treatment in an experimental setting [153]. Moreover, drugs such as metformin and resveratrol that modulate AMPK signaling can correct abnormalities of autophagy and enhance insulin sensitivity [150,154]. SIRT1 activators such as resveratrol are also useful in promoting autophagy [154]. The development of more specific mTOR inhibitors (Rapalogs) and their combination with other modulators of autophagy can potentially provide better therapeutic avenues for the treatment of insulin resistance and other components of the CMS. The beneficial effects of exercise on stimulation of autophagy and improvement in insulin sensitivity [155] provide support for lifestyle intervention as an important component in targeting autophagy to improve insulin sensitivity and other abnormalities associated with the CMS.

    1.8 Conclusion

    The CMS is increasing in parallel with a rising incidence of overweight/obesity in the United States and worldwide. Although genetic and epigenetic factors are important determinants, consumption of high fat/refined sugars (WD) and decreased physical activity are the major drivers of both obesity and the CMS. Both sedentary lifestyle and WD are associated with maladaptive/impaired autophagy and impaired systemic and tissue insulin metabolic signaling. Transition from obesity to the CMS and further to development of T2DM, CVD, and CKD is caused by progressive dysregulated autophagy and deterioration of insulin sensitivity. Inappropriate activation of the RAAS and associated oxidative stress and maladaptive immune inflammatory responses contribute significantly to dysregulated/impaired autophagy and the development of insulin resistance in overweight/obese states. Further, impaired/dysregulated autophagy itself causes inflammatory responses and insulin resistance resulting in a positive feed-forward progression of the CMS. Autophagy as a therapeutic target in the CMS could potentially be accomplished by targeting inappropriate activation of RAAS and the mTOR1-AMPK-sirtuin signaling complex, along with lifestyle modification in a context-dependent manner.

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