Glucoraphanin: a broccoli sprout extract that ameliorates obesity-induced inflammation and insulin resistance

Abstract

Obesity is a low-grade sustained inflammatory state that causes oxidative stress in different metabolic tissues, which leads to insulin resistance and nonalcoholic fatty liver disease (NAFLD). Particularly, obesity-induced metabolic endotoxemia plays an important role in the pathogenesis of insulin resistance and inflammation. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of antioxidant signaling that serves as a primary cellular defense against the cytotoxic effects of oxidative stress. Pharmacological stimulation of Nrf2 mitigates obesity and insulin resistance in mice; however, Nrf2 activators are not clinically available due to biosafety concerns. A recent study demonstrated that glucoraphanin, a precursor of the Nrf2 activator sulforaphane, ameliorates obesity by enhancing energy expenditure and browning of white adipose tissue, and attenuates obesity-related inflammation and insulin resistance by polarizing M2 macrophages and reducing metabolic endotoxemia. Thus, this review focuses on the efficiency and safety of glucoraphanin in alleviating obesity, insulin resistance, and NAFLD. Abbreviations: ALT, Alanine aminotransferase; AMPK, AMP-activated protein kinase; ATMs, Adipose tissue macrophages; BAT, Brown adipose tissue; CDDO-Im, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid-imidazolide; CDDO-Me, CDDO-methyl ester; DIO, High-fat-diet-induced obese; FFA, Free fatty acid; FGF, Fibroblast growth factor; GTP, Glutamyl transpeptidase; HFD, High-fat diet; IKKβ, Inhibitor of κB-kinase β; IL, Interleukin; JNK, C-Jun N-terminal kinase; KD, Knockdown; Keap1, Kelch-like ECH-associated protein 1; KO, Knockout; LPS, Lipopolysaccharide; NADPH, Nicotinamide adenine dinucleotide phosphate; NAFLD, Non-alcoholic fatty liver disease; NF-κB, Nuclear factor-κB; Nrf2, Nuclear factor E2-related factor 2; ROS, Reactive oxygen species; T2D, Type 2 diabetes; TLR, Toll-like receptor; TNF, tumor necrosis factor; UCP, Uncoupling protein; WAT, White adipose tissue.

Keywords: Nrf2; Obesity; glucoraphanin; insulin resistance; metabolic endotoxemia.

Figure 1.

The Nrf2–Keap1 signaling pathway. Under normal conditions, Keap1 binds to Nrf2 and Nrf2 is polyubiquitylated by the Cullin3-based E3 ligase complex, leading to ubiquitination and subsequent degradation of Nrf2. Upon exposure to electrophilic and oxidative stress, Nrf2 detaches from its repressor Keap1, and is translocated from the cytoplasm into the nucleus. Nrf2 becomes stabilized, and then nuclear Nrf2 binds to the antioxidant response element (ARE) with members of the small Maf family in the promoter regions of a battery of genes that encode antioxidant and phase 2 detoxifying enzymes, including HO-1, Prdx1, Nqo1, and Gst.

Figure 2.

Schematic representation of the beneficial effects of glucoraphanin on obesity. Glucoraphanin is hydrolyzed by gut microbiota-derived myrosinase into bioactive sulforaphane, leading to the following: (1) Increased adipose tissue browning to augment energy consumption. (2) Enhanced M2 macrophage polarization resulting in M2-dominant shift of macrophages in the liver and white adipose tissue. (3) Improved ‘high-fat’ gut bacterial flora, with subsequent reduction of blood LPS levels and metabolic endotoxemia. Consequently, glucoraphanin attenuated the diet-induced adiposity and obesity-related inflammation and insulin resistance.