Toward a unifying hypothesis of metabolic syndrome

Abstract

Despite a lack of consistent diagnostic criteria, the metabolic syndrome (MetS) is increasingly evident in children and adolescents, portending a tsunami of chronic disease and mortality as this generation ages. The diagnostic criteria for MetS apply absolute cutoffs to continuous variables and fail to take into account aging, pubertal changes, and race/ethnicity. We attempt to define MetS mechanistically to determine its specific etiologies and to identify targets for therapy. Whereas the majority of studies document a relationship of visceral fat to insulin resistance, ectopic liver fat correlates better with dysfunctional insulin dynamics from which the rest of MetS derives. In contrast to the systemic metabolism of glucose, the liver is the primary metabolic clearinghouse for 4 specific foodstuffs that have been associated with the development of MetS: trans-fats, branched-chain amino acids, ethanol, and fructose. These 4 substrates (1) are not insulin regulated and (2) deliver metabolic intermediates to hepatic mitochondria without an appropriate "pop-off" mechanism for excess substrate, enhancing lipogenesis and ectopic adipose storage. Excessive fatty acid derivatives interfere with hepatic insulin signal transduction. Reactive oxygen species accumulate, which cannot be quenched by adjacent peroxisomes; these reactive oxygen species reach the endoplasmic reticulum, leading to a compensatory process termed the "unfolded protein response," driving further insulin resistance and eventually insulin deficiency. No obvious drug target exists in this pathway; thus, the only rational therapeutic approaches remain (1) altering hepatic substrate availability (dietary modification), (2) reducing hepatic substrate flux (high fiber), or (3) increasing mitochondrial efficiency (exercise).

FIGURE 1

Selective IR in the liver. Under normal conditions, dietary glucose stimulates insulin secretion from the pancreatic β-cells. Insulin then travels directly to the liver via the portal vein, where it binds to the insulin receptor and elicits 2 key actions at the level of gene transcription. First, insulin stimulates the phosphorylation of FoxO1, which prevents it from entering the nucleus and thus diminishes the expression of genes required for gluconeogenesis; the net effect is diminished hepatic glucose output. Second, insulin activates the transcription factor SREBP-1c, which in turn increases the transcription of genes required for fatty acid and TG biosynthesis; the net effect is DNL. In the liver of individuals with MetS, insulin fails to decrease gluconeogenesis because of decreased signaling through the FoxO1 pathway but continues to stimulate the production of fatty acids and TGs through the SREBP-1c pathway. Resistance to the FoxO1 pathway leads to dysglycemia and subsequent compensatory hyperinsulinemia, whereas sensitivity to the SREBP-1c pathway leads to DNL, intrahepatic lipid deposition, and dyslipidemia/hypertriglyceridemia, enhancing ectopic lipid deposition. (Adapted from Brown and Goldstein.)

FIGURE 2

A, Hepatic BCAA metabolism. BCAAs induce: excess formation of alanine, which serves as a substrate for gluconeogenesis, contributing to hyperglycemia; excess formation of α-ketoacids, leading to increased levels of C5 and C3 acylcarnitine levels and subsequently excess formation of malonyl-CoA, which inhibits β-oxidation; hepatic lipid droplet formation and steatosis; activation of mTOR and its downstream target S6K, which contributes to serine phosphorylation of IRS-1 and hepatic IR, which in turn promotes hyperinsulinemia and influences substrate deposition into fat; and export of free fatty acids, which leads to VLDL formation and muscle IR. α-KG, α-ketoglutarate; BCKA, branched-chain keto acid; pSer-IRS-1, serine phosphorylated IRS-1; S6K, S6 kinase. B, Hepatic ethanol metabolism. Ethanol induces: DNL and dyslipidemia; JNK-1 activation, which serine phosphorylates hepatic IRS-1, rendering it inactive, and contributing to hepatic IR, which promotes hyperinsulinemia and influences substrate deposition into fat; hepatic lipid droplet formation, leading to steatosis; and stimulation of the reward pathway, promoting continuous consumption. (Reproduced from Lustig.) ACC, acetyl CoA carboxylase; ACL, adenosine triphosphate citrate lyase; FAS, fatty acid synthase; MTP, microsomal transfer protein. C, Hepatic fructose metabolism. Fructose induces substrate-dependent phosphate depletion, which increases uric acid and contributes to hypertension through inhibition of endothelial nitric oxide synthase and reduction of NO; DNL and dyslipidemia; hepatic lipid droplet formation and steatosis; muscle IR; JNK-1 activation, contributing to hepatic IR, which promotes hyperinsulinemia and influences substrate deposition into fat; and CNS hyperinsulinemia, which antagonizes central leptin signaling and promotes continued energy intake. (Reproduced from Lustig.) ACC, acetyl CoA carboxylase; ACL, adenosine triphosphate citrate lyase; ACSS2, acyl-CoA synthetase short-chain family member 2; AMP, adenosine monophosphate; BP, blood pressure; CNS, central nervous system; FAS, fatty acid synthase; Glut5, glucose transporter 5; MTP, microsomal transfer protein; NO, nitric oxide; pSer-IRS-1, serine phosphorylated IRS-1.

FIGURE 3

Molecular renditions of (A) glucose and (B) fructose, in the linear, chair, and space-occupying projections. In the linear form, both glucose and fructose possess a reactive aldehyde or one ketone moiety, which can bind nonenzymatically to freely available amino groups of proteins. At normal body temperature and pH, the chair form of glucose predominates. This conformation is a glucopyranose (6-membered ring), with equatorial hydroxyl groups and is molecularly stable, which limits its protein reactivity. However, the chair form of fructose is a fructofuranose (5-membered ring) with 2 axial hydroxymethyl groups that exert allosteric and ionic forces on the unstable furanose ring, which favors the linear form. Thus, at normal body temperature and pH, the majority of fructose exists in the linear form and is more reactive with proteins than is glucose. (Reproduced from Lim et al.)

FIGURE 4

Intracellular ROS formation and consequences of fructose metabolism. Dietary fructose, because of its metabolic processing in the mitochondria and the fructosylation of protein ε-amino groups via the Maillard reaction, and circulating inflammatory cytokines, because of their receptor-mediated activation of NADPH oxidase, increase intracellular levels of ROS. In the absence of sufficient peroxisomal quenching and degradation, the ROS moieties lead to the UPR response, causing either cell death (apoptosis) or cellular/metabolic dysfunction. The formation of acetyl-CoA also leads to lipid deposition and IR through the activation of inflammatory pathways as described in the text. (Adapted from Parola and Marra.) NADPH, nicotinamide adenine dinucleotide phosphate; pSer-IRS-1, serine phosphorylated IRS-1.