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Review
. 2022 Feb 2;10(3):825-847.
doi: 10.1016/j.gendis.2021.12.011. eCollection 2023 May.

Friend or foe for obesity: How hepatokines remodel adipose tissues and translational perspective

Yao Zhang  1 , Yibing Wang  2 , Junli Liu  1
Affiliations
Review

Friend or foe for obesity: How hepatokines remodel adipose tissues and translational perspective

Yao Zhang et al. Genes Dis. .

Abstract

Due to excess energy intake and a sedentary lifestyle, the prevalence of obesity is rising steadily and has emerged as a global public health problem. Adipose tissue undergoes structural remodeling and dysfunction in the obese state. Secreted proteins derived from the liver, also termed as hepatokines, exert multiple effects on adipose tissue remodeling and the development of obesity, and has drawn extensive attention for their therapeutic potential in the treatment of obesity and related diseases. Several novel hepatokines and their functions on systemic metabolism have been interrogated recently as well. The drug development programs targeting hepatokines also have shown inspiring benefits in obesity treatment. In this review, we outline how adipose tissue changes during obesity. Then, we summarize and critically analyze the novel findings on the effects of metabolic "beneficial" and metabolic "harmful" hepatokines to adipose tissue. We also discuss the in-depth molecular mechanism that hepatokines may mediate the liver-adipose tissue crosstalk, the novel technologies targeting hepatokines and their receptors in vivo to explore their functions, and the potential application of these interventions in clinical practice.

Keywords: FGF21; Hepatokine; Liver-adipose tissue crosstalk; Obesity; Therapeutic strategy.

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Figures

Figure 1
Figure 1
The metabolic effects of hepatokines on adipose tissue. During the healthy state, the liver can secret hepatokines to the circulation, then hepatokines exert roles in both white and brown adipose tissue (WAT and BAT) physiological function, such as energy storing and expenditure. During energy stress, such as high-fat diet, calorie restriction, fasting, and refeed, several modulators including insulin, glucose, and glucagon levels alter, thereby disrupt the expression and secretion of hepatokines. The dysregulated hepatokines then circulate to adipose tissue, resulting in adipocytes hyperplasia and hypertrophy, reducing insulin sensitivity, increasing inflammation, decreasing energy expenditure, promoting fibrosis, and altering adipokine profiles.
Figure 2
Figure 2
The functional roles of hepatokines on adipose tissue metabolism. Metabolic beneficial or harmful hepatokines bind with and signal through their receptors on adipose tissue and influence downstream pathway, further regulate multifaceted function of adipocytes, including glucose uptake, thermogenesis, lipolysis, inflammation, fibrosis, adipogenesis, proliferation and lipogenesis, which finally modulate fat accumulation and insulin sensitivity in adipose tissue and whole-body metabolism.
Figure 3
Figure 3
The clinical application of hepatokines. The hepatokines can be known as biomarkers and pharmacological targets in obesity diagnosis and treatment. Noninvasive blood tests evaluating hepatokines levels can help clinical doctors predict and diagnose the metabolic disorder, and provide information for a likely outcome. There are four strategies targeting hepatokines applied in clinical practice. Gene therapy is designed to regulate the expression of hepatokines. Vupanorsen is N-acetylgalactosamine conjugates antisense oligonucleotide thereby degrade ANGPTL3 mRNA. Injection recombinant proteins, such as LY2405319, a PEGylated FGF21, into the circulation can also mimic its role. Besides, agonists activating the receptor of hepatokines, such as NGM313, an agonist towards FGFR1/Klothoβ complex, also restore metabolic homeostasis. At last, neutralizing antibodies are produced to block excess hepatokines. Evinacumab is such a monoclonal antibody against ANGPTL3.
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