A picture is worth a thousand words. As this diagram astutely shows, decreases in exercise, fiber, polyphenols, O3/O6 intake and tissue ratios, and caloric restriction all lead to the metabolic syndrome (abdominal obesity, dyslipidemia, hypertension, and a chronic inflammatory and prothrombotic state), chronic disease, and early death.
Resveratrol inhibits PDEs, leading to increased cAMP levels, Epac1 activation, elevated intracellular calcium, and AMPK activation. Calorie restriction and other behavioral inputs also activate AMPK. Downstream of AMPK, an increase in NAD+levels leads to SIRT1 activation, which promotes beneficial metabolic changes primarily through deacetylation and activation of PGC-1α. In a parallel pathway, increased cAMP levels activate PKA, which directly phosphorylates and activates SIRT1. SIRT1 activation by either pathway, as well as potential activation of other NAD+-dependent enzymes, can lead to numerous physiologic outputs. Blue box (top) highlights findings reported by Park et al. (2012); orange box (bottom) highlights pathway components previously identified that reside downstream of those identified by Park et al., as well as some of the reported and theoretical outputs of the signaling pathways detailed above. Blue arrows indicate the linear pathway proposed by Park et al.; dashed lines indicate molecular connections previously reported. PDE, phosphodiesterase; cAMP, cyclic AMP; Epac1, cAMP-regulated guanine nucleotide exchange factor 1; CamKKβ, calcium/calmodulin-dependent kinase kinase beta; AMPK, AMP-activated protein kinase; PKA, protein kinase A; NAD+, nicotinamide adenine dinucleotide; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator-1 alpha; ROS, reactive oxygen species.
Mechanisms modulating oxidant/antioxidant balance in obesity. On the left-hand side are shown mechanisms underlying oxidative stress in obesity and obesity-associated complications, while on the right-hand side are shown strategies improving body antioxidant machinery (see text for details). Dotted lines: inhibitory effect. Solid lines: stimulatory effect.
AGEs: advanced glycation end products; ATF: NF-κB, activating transcription factor; CPT2: carnitine palmitoyltransferase 2; CREB: cyclic AMP response element binding; ER: endoplasmic reticulum; FAS: fatty acid synthase; FoxO: forkhead box, sub-group O; HO-1: heme oxygenase-1; iNOS: inducible nitric oxide synthase; LPS: lipopolysaccharide MCP-1: monocyte chemotactic protein-1; miR: microRNA; NF-κB: nuclear factor-κB; Nox: NADPH oxidase; PKC: protein kinase C; PPAR-α: peroxisome proliferator-activated receptor-α; SCD1: stearoyl-CoA desaturase-1; SIRT: sirtuin; SREBP1: sucrose responsive element binding protein1; STAT3: signal transducer and activator of transcription 3; TGF-β: transforming growth factor-β; TNF-α: tumor necrosis factor-α.