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. 2023 Mar 13;59(3):561. doi: 10.3390/medicina59030561

Figure 1.

Figure 1

From Reaven’s simplified syndrome X to the complicated metabolic syndrome (MetS) reloaded. This image illustrates the simple Reaven’s Syndrome X (far left) to the complex MetS reloaded and its multiple risk factors. According to Reaven, the letter “X” was originally chosen because at the time coronary artery disease (CAD) and/or cerebrocardiovascular disease (CCVD) was a relatively unknown risk of human insulin resistance. Syndrome X was later termed the MetS by the National Cholesterol Education Program Adult Treatment Panel III and Grundy et al., 2002 and 2004, respectively. Hyperlipidemia (lower left arm), hyperinsulinemia, and hyperamylinemia (lower right arm), hypertension (essential) (upper right arm), and hyperglycemia with or without manifest T2DM (upper left arm) in the MetS reloaded represent the four arms to the central capital letter X. Importantly, visceral or central obesity is thought to be a major driver of this syndrome and is related to the emergent science of visceral adipose tissue (VAT) with adipocyte-derived adipokines and macrophage-derived cytokines/chemokines. Additionally, it is important to note the novel adipocyte and macrophage-derived exosomes with their novel signaling microRNAs (miRNAs) and long-non-coding RNAs (lncRNAs), which are capable of both paracrine and endocrine (inter-organ and long-distant) signaling in addition to the signaling via peripheral cytokine/chemokine adipokine network due to excessive meta-inflammation within VAT depots. Note that insulin resistance (IR) and leptin resistance (LR or Lr) (ILR) are placed centrally within the letter X. Importantly, note the red bold arrow connecting central visceral obesity to the central ILR within the letter X that is related to increased meta-inflammation. Also, note how the aberrant mitochondria (aMt) (a constant finding in obese and diabetic models) and hyperhomocyteinemia (HHcy) are flanking the central insulin and leptin resistance (ILR) that reflects impaired folate-mediated one-carbon metabolism (FOCM). Additionally, note the important role of microbiota dysbiosis and its emerging role associated with obesity and the MetS reloaded. Note the relationship between the HPA axis and the RAAS with increased sodium retention (*).Ang II = angiotensin II; CAD = coronary artery disease; CKD = chronic kidney disease; CCVD = cerebrocardiovascular disease; DPN = diabetic peripheral neuropathy; eNOS = endothelial nitric oxide synthase; ER = endoplasmic reticulum; FFA = free fatty acids; Hcy = homocysteine; ILR = insulin/leptin resistance; LOAD = late-onset Alzheimer’s disease; lncRNAs = long non-cording RNAs; HPA = hypothalamic–pituitary–adrenal axis; LPS = lipopolysaccharide; LR = leptin resistance—selective Lr; miRNAs = micro ribonucleic acids; Mt = mitochondria; NADPH Ox = nicotinamide adenine dinucleotide phosphate oxidase; NAFLD = non-alcoholic fatty liver disease; NO = nitric oxide; Non-HDL-C = non-high-density lipoprotein-cholesterol; O2 = oxygen; oxLDL-C = oxidized low density lipoprotein-cholesterol; PAI-1 = plasminogen activator inhibitor -1; PCOS = polycystic ovary syndrome; RAAS = renin-angiotensin-aldosterone-system; RNA = ribonucleic acid; RONSS = reactive oxygen, nitrogen, sulfur species; RSI = reactive species interactome; sdLDL-C = small dense low-density lipoprotein-cholesterol; SNS = sympathetic nervous system; Trigs = triglycerides; XO = xanthine oxidase.