GC‐(4→8)‐GCG, A Proanthocyanidin Dimer from Camellia ptilophylla, Modulates Obesity and Adipose Tissue Inflammation in High‐Fat Diet Induced Obese Mice

Abstract

Scope: Excessive fat accumulation in adipose tissue leads to obesity and related chronic inflammation. This study aims to examine the effects of gallocatechin -(4→8)-gallocatechin-3-O-gallate (GC-(4→8)-GCG), a main proanthocyanidin dimer from Camellia ptilophylla (Cocoa tea), on adipocyteand adipose-related inflammation in vivo and in vitro. Methods and results: C57BL/6 mice are fed a high-fat diet (HFD) and GC-(4→8)-GCG (40 or 80 mg kg −1 d −1 ) for 8 weeks. The metabolic profiles, adipose tissue hypertrophy, macrophage infiltration, and inflammatory cytokine production are investigated. Additionally, 3T3-L1 preadipocytes are utilized to investigate the effect of GC-(4→8)-GCG on preadipocyte differentiation and the tumor necrosis factor (TNF)-α-stimulated inflammatory response in vitro. GC-(4→8)-GCG supplementation decreases HFD-induced epididymal white adipose tissue (eWAT) hypertrophy, suppresses proinflammatory cytokine production and macrophage infiltration in eWAT, and improves insulin sensitivity in HFD-induced obese mice. In vitro, GC-(4→8)-GCG shows a strong anti-adipogenic potential in 3T3-L1 preadipocyte by inhibiting the expression of key adipogenic transcription factors and decreasing the production of proinflammatory cytokines by inhibiting the activation of the nuclear factor (NF)-κB, Janus tyrosine kinase/signal transducer and activator of transcription (JAK/STAT3) and mitogen-activated protein kinase (MAPK) signaling pathways. Conclusion: GC-(4→8)-GCG can modulate obesity and improve obesity-related insulin resistance by inhibiting preadipocyte differentiation and the related proinflammatory responses.

Impact of Dietary Flavanols on Microbiota, Immunity and Inflammation in Metabolic Diseases

“…In agreement with all of the above, a number of works in murine models fed with high fat diets (HFD) ( Table 2 ) supplemented with different pure flavanols (EGCG or proanthocyanidin dimer) or flavanol-rich foods (cocoa, green tea or grape seeds) have also shown a reduction in the inflammatory situation together with a diminished macrophage infiltration [ 79 , 80 , 82 , 83 , 84 , 85 ] ( Table 1 and Table 2 ). At molecular level, decreased values of pro-inflammatory cytokines (TNF-α, IL-6 or MCP-1 by ~40–90%), and diminished pro-inflammatory enzymatic activities (iNOS, COX-2, adipose-specific phospholipase A2 by 80%, 55% and 53%, respectively) were associated to the downregulation of key proteins for the inflammatory process (NF-κB, MAPKs, TLR-4 and signal transducer and activator of transcription 3 [STAT3]), reduced macrophage infiltration in the adipose tissue, and a switch towards the less inflammatory M2-like phenotype macrophages [ 79 , 80 , 82 , 83 , 84 , 85 ]. Moreover, these outcomes have been related to a reduced endotoxemia by restoring the gut barrier [ 83 ], improved insulin signaling [ 80 , 82 ], as well as glucose and lipid metabolism [ 80 , 84 ], and redox status [ 84 ].…”

Metabolic Impact of Flavonoids Consumption in Obesity: From Central to Peripheral

“…The activation of the mTOR/S6K phosphorylates and desensitizes the insulin receptor substrate 1 (IRS1) [ 157 ]. In a similar way, GC-(4→8)-GCG, a proanthocyanidin dimer from Camellia ptilophylla improved hepatic steatosis and hyperlipidemia in HFD-induced obese mice [ 158 ].…”

“…In rodents, the administration of grape seed-derived proanthocyanins to Wistar rats reduced the body weight by limiting food intake and activating EE in scWAT [ 168 ] and it has been widely described that in rodent models of obesity, flavanols are able to affect the lipid metabolism of WAT and BAT. Global effects of flavanols in adipose tissues lead to a decrease in adiposity, specially of the WAT depots and in adipocyte size by reducing adipogenesis, the release of adipokines such as leptin and resistin, the modulation of lipid metabolism and the induction of browning [ 153 , 155 , 158 , 169 , 170 , 171 , 172 , 173 , 174 ]. In BAT, flavanols caused the activation of thermogenesis and FAO [ 172 , 173 , 174 , 175 , 176 ].…”

“…Besides its effects in the liver, the GC-(4→8)-GCG inhibited the expansion of all WAT depots in HFD fed mice. Adipocytes from eWAT were smaller and some of the main adipocyte-associated transcription markers were downregulated ( Srebp1c, C/ebpα and Pparγ ), thus indicating a better WAT functionality [ 158 ]. The GC-(4→8)-GCG-supplemented mice showed an upregulation of the adiponectin and a downregulation of the leptin mRNA levels as well as an improved inflammatory profile with less macrophage infiltration [ 158 ].…”

Water Extract of Lysimachia christinae Inhibits Trabecular Bone Loss and Fat Accumulation in Ovariectomized Mice

“…Reportedly, except for 3 components (quinic acid, schaftoside, and betaine), 13 individual components present inhibitory activities on osteoclast differentiation in vitro and OVX-or glucocorticoid-induced osteoporosis in animal models [43][44][45]. Additionally, some constituents possess anti-adipogenic activity by inhibiting the expression of key adipogenic transcription factors, decreasing the production of pro-inflammatory cytokines in 3T3-L1 cells, or by suppressing fat accumulation in animal models fed a high-fat diet [46,47]. Given that exposure of each WELC component on in vivo target tissue would be lower than the effective dose of individual components, WELC might demonstrate pharmacological efficacy in osteoporosis and obesity through additive and synergistic effects of these components present in WELC.…”