Calorie Restriction as a New Treatment of Inflammatory Diseases

Abstract

Immoderate calorie intake coupled with a sedentary lifestyle are major determinants of health issues and inflammatory diseases in modern society. The balance between energy consumption and energy expenditure is critical for longevity. Excessive energy intake and adiposity cause systemic inflammation, whereas calorie restriction (CR) without malnutrition, exerts a potent anti-inflammatory effect. The objective of this review was to provide an overview of different strategies used to reduce calorie intake, discuss physiological mechanisms by which CR might lead to improved health outcomes, and summarize the present knowledge about inflammatory diseases. We discuss emerging data of observational studies and randomized clinical trials on CR that have been shown to reduce inflammation and improve human health.

Keywords: autophagy; caloric restriction; endoplasmic reticulum stress; fasting; gut microbiota; inflammatory disease; metabolic switch.

FIGURE 1

Calorie restriction and anti-inflammatory effects. Calorie restriction (CR) promotes a switch in gut microbiota composition and favors protecting bacteria which produce anti-inflammatory SCFAs, improve intestinal integrity and permeability, and limit bacterial toxin internalization. CR is detected by the decrease in serum glucose concentration and subsequent decrease of mitochondrial activity. On the one hand, hypoglycemia decreases anabolic hormones (e.g. insulin, GH, and IGF1), as well as sex and thyroid hormones, increases the expression of the catabolic cortisol, and subsequently inhibits the MAPK pathway (i.e. RAS/RAF/MEK/ERK) and the PI3K/Akt/mTOR pathway. On the other hand, the inhibition of ERK avoids mTOR activation and subsequently induces autophagy activity, which contributes to the suppression of inflammation by downregulation of both IFN and proinflammatory cytokine responses. Inhibition of mTOR also inhibits HIF1, a transcription factor involved in the upregulation of the inflammation related genes (e.g. cytokines, chemokines, iNOS, and COX-2) as well as in the mediation of the proinflammatory effect of ROS and the activation of NF-κB (34, 35). Moreover, the decrease of mitochondrial activity activates AMPK and downstream regulators such as sirtuins and transcription factors (e.g. FoxO3A and FoxO1) and subsequently activates PGC-1α. PGC-1α is a major inhibitor of NF-kB and activates the anti-inflammatory nuclear receptor PPAR. The activation of AMPK activates the nuclear factor-E2 related-factor 2 (NRF2)-dependent response to oxidative stress, which extends the inhibition of NF-kB and promotes autophagy-dependent repression of inflammation. Moreover, activation of AMPK decreases reticulum stress and triggers the switch from glucose to ketones which is a global metabolism modification consisting of 1) the decrease of the anabolic pathways and glucose utilization, 2) the increase of adipose tissue lipolysis and the production of ketone bodies (e.g. BHB), and also 3) modulation of adipokine and hormone secretion by adipose tissue. In summary, BHB and adiponectin inhibit inflammation through activation of the AMPK regulation network. In contrast, circulating amounts of leptin, a proinflammatory hormone produced by the white adipose tissue decreased. Therefore, CR-dependent inhibition of NF-kB and of PI3K signaling pathways contribute to the maintenance of the oxidative status and have an anti-inflammatory effect through the inhibition of NLRP3, the decrease of proinflammatory markers, the increase of anti-inflammatory IL-10, and the improvement of anti-inflammatory Treg and M2 cells polarization. Akt, AKT serine/threonine kinase; AMPK, AMP-activated protein kinase; BHB, β-hydroxybutyrate; CCL2, C-C motif chemokine ligand 2; COX-2, cyclooxygenase-2; CR, calorie restriction; CRP, C-reactive protein; CXCL9, C-X-C motif chemokine ligand 9; ER stress, endoplasmic reticulum stress; ERK, extracellular signal-regulated kinase; FOXO, forkhead box O; f-PUFA, free-PUFAs; GH, growth hormone; GPx, glutathione peroxidase; GSH, glutathione; G-to-K switchover, glucose-ketone switchover; HIF1, hypoxia-inducible factor 1; HO-1, heme oxygenase-1; IGF-1, insulin-like growth factor-1; IGF-R, insulin-like growth factor-receptor; iNOS, inductible nitric oxide synthase; LKB1, liver kinase B1; MEK, Raf, Ras, serine/threonine kinase; MnSOD, manganese superoxide dismutase; mtETC, mitochondrial electron transport chain; mTORC1/2, mammalian target of rapamycin-1/2; mtROS, mitochondrial reactive oxygen species; NLRP3, pyrin-containing receptor 3; NRF2, nuclear factor erythroid 2-related factor 2; PGC1-α, peroxisome proliferator-activated receptor-γ coactivator 1-α; PI3K, phosphatidylinositol 3-kinase; PPAR, peroxisome proliferator-activated receptor; PPP, pentose phosphate pathway; PRx, peroxiredoxin; ROS, reactive oxygen species; SOD2, superoxide dismutase 2; T3, triiodothyronine; TLR, toll-like receptor.