Targeting the fat-liver crosstalk for therapeutic intervention of obesity-related metabolic complications

Abstract

The obese population is growing at an alarming rate worldwide. As obesity is a major risk factor of multiple chronic metabolic complications, including diabetes and cardiovascular diseases, innovative and affordable strategies to control and cure obesity and related metabolic complications are urgently needed to end the pandemic. Growing evidence suggests that the active interplay between the liver and adipose tissue mediated by hormones and receptors is crucial in maintaining energy homeostasis. However, the understanding of the dynamic communication between these two distant endocrine organs is still limited. Intriguingly, our laboratory’s global gene profiling analysis showed that dietinduced obesity in mice is correlated with the downregulation of two novel targets, lipocalin (LCN) 14 – a lipocalin mainly expressed in adipose tissue and G protein coupled receptor (GPR) 110 – an orphan class B G protein-coupled receptor exclusively expressed in liver. The major objective of this study was therefore to investigate the pathophysiological roles of LCN14 and GPR110 in obesity-related metabolic complications and explore potential therapeutic strategies for metabolic diseases through understanding their physiological roles in fat-liver crosstalk.

To investigate the role of LCN14 in the progression of obesity-induced diabetes, we restored LCN14 expression in DIO mice with the use of recombinant adenoassociated virus (rAAV) gene delivery. The findings suggested that LCN14 restoration ameliorated hyperglycemia by inhibiting hepatic gluconeogenesis and enhancing insulin sensitivity in the liver and adipose tissue. Furthermore, we demonstrated that LCN14 can reduce hepatic glucose production through suppression of glycerol efflux in adipocytes.

To reveal the role of hepatic GPR110, homozygous Gpr110 knockout (KO) mice were generated. When fed with high-fat diet (HFD), Gpr110 KO mice exhibited a metabolically healthier phenotype as compared to their wildtype littermates; whereas adenovirus-mediated transient overexpression of GPR110 in DIO mice exacerbated glucose intolerance. Importantly, we demonstrated that the anti-obesity phenotype was attributed to the FGF21-adiponectin axis. Ablation of GPR110 in mice induces cAMP-PKA pathway and subsequently upregulates hepatic secretory FGF21 protein, and thereby increases serum adiponectin level.

These findings collectively provide evidence that LCN14 and GPR110 are crucial players in whole-body energy homeostasis through mediating crosstalk between the liver and adipose tissue. LCN14 may serve as a potential therapy to treat hyperglycemia in obese patients. Manipulation of GPR110 downstream pathways may potentially reduce weight gain in overweight patients by enhancing whole-body energy expenditure. Therefore, interventions that mimic LCN14 and antagonists of hepatic GPR110 may represent potential therapeutic strategies to combat obesity-related metabolic complications.