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

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.

Exercise training-induced changes in exerkine concentrations may be relevant to the metabolic control of type 2 diabetes mellitus patients:A systematic review and meta-analysis of randomized controlled trials

Background:This study investigates the effects of exercise training on exerkines in patients with type 2 diabetes mellitus to determine the optimal exercise prescription.Methods:A systematic search for relevant studies was performed in 3 databases.Randomized controlled trials investigating the effects of exercise training on at least one of the following exerkines were included:adiponectin,apelin,brain-derived neurotrophic factor,fetuin-A,fibroblast growth factor-21,follistatin,ghrelin,interleukin(IL)-6,IL-8,IL-10,IL-15,IL-18,leptin,myostatin,omentin,resistin,retinol-binding protein 4,tumor necrosis factor-α,and visfatin.Results:Forty randomized controlled trials were selected for data extraction(n=2160).Exercise training induces changes in adiponectin,fetuin-A,fibroblast growth factor-21,IL-6,IL-10,leptin,resistin,and tumor necrosis factor-a levels but has no significant effects on apelin,IL-18,and ghrelin compared to controls.Physical exercise training favored large and positive changes in pooled exerkines(i.e.,an overall effect size calculated from several exerkine s)(Hedge’s g=1.02,95%confidence interval(95%CI):0.76-1.28),which in turn were related to changes in glycated hemoglobin(mean difference(MD)=-0.81%,95%CI:-0.95%to-0.67%),fasting glucose(MD=-23.43 mg/dL,95%CI:-30.07 mg/dL to-16.80 mg/dL),waist circumference(MD=-3.04 cm,95%CI:-4.02 cm to-2.07 cm),and body mass(MD=-1.93 kg,95%CI:-2.00 kg to-1.86 kg).Slightly stronger effects were observed with aerobic,resistance,or high-intensity interval protocols at moderate-to vigorous-intensity and with programs longer than 24 weeks that comprise at least 3 sessions per week and more than 60 min per session.Conclusion:Exercise training represents an anti-inflammatory therapy and metabolism-improving strategy with minimal side effects for patients with type 2 diabetes mellitus.

Newly discovered endocrine functions of the liver

The liver,the largest solid visceral organ of the body,has numerous endocrine functions,such as direct hormone and hepatokine production,hormone metabolism,synthesis of binding proteins,and processing and redistribution of metabolic fuels.In the last 10 years,many new endocrine functions of the liver have been discovered.Advances in the classical endocrine functions include delineation of mechanisms of liver production of endocrine hormones[including 25-hydroxyvitamin D,insulin-like growth factor 1(IGF-1),and angiotensinogen],hepatic metabolism of hormones(including thyroid hormones,glucagon-like peptide-1,and steroid hormones),and actions of specific binding proteins to glucocorticoids,sex steroids,and thyroid hormones.These studies have furthered insight into cirrhosis-associated endocrinopathies,such as hypogonadism,osteoporosis,IGF-1 deficiency,vitamin D deficiency,alterations in glucose and lipid homeostasis,and controversially relative adrenal insufficiency.Several novel endocrine functions of the liver have also been unraveled,elucidating the liver’s key negative feedback regulatory role in the pancreaticαcell-liver axis,which regulates pancreaticαcell mass,glucagon secretion,and circulating amino acid levels.Betatrophin and other hepatokines,such as fetuin-A and fibroblast growth factor 21,have also been discovered to play important endocrine roles in modulating insulin sensitivity,lipid metabolism,and body weight.It is expected that more endocrine functions of the liver will be revealed in the near future.

The Association of Non Viral Liver Diseases from NAFLD to NASH to HCC with the Pandemic of Obesity,Type 2 Diabetes,or Diabesity&Metabolic Syndrome Etiopathogenetic Correlation along with Uti­lization for Diagnostic&Therapeutic Purposes-A Systematic Review

Earlier we have been reviewing the etiopathogenesis(EP)of obesity,type2 Diabetes mellitus(T2DM),Metabolic Syndrome(MetS),Non Alcoholic Fatty Acid Liver Disease(NAFLD)non alcoholic steatohepapititis(NASH),along with its propagation to Hepatocellular carcinoma(HCC)in addition to their therapies exhaustively.T2DM continues to be a major health issue with reaching epidemic to pandemic proportions.Liver disease includes a spectrum of liver injury varying from isolated steatosis known as Non Alcoholic Fatty Acid Liver Disease(NAFLD)to HCC.Clinically it has been observed that the coexistence of NAFLD as well as T2DM is prevalent.T2DM aids in the biological events that results in escalation of robustness of NAFLD that constitutes the primary etiology of chronic liver diseases.In the past 2 decades the incidence of nonviral NAFLD/NASH,obtained HCC has been escalating at a fast pace.In view of no appropriate agents for therapy of NAFLD/NASH,a thiazolidenedione group of drug pioglitazone used for T2DM therapy is utilized occasionally.Thus here we conducted a systematic review utilizing search engine pubmed,google scholar;web of science;embase;Cochrane review libraryutilizingtheMeSHterms like T2DM;MetS;NAFLD;NASH;HCC;WAT;BAT;VisceralAT;Obesity;BMI;Adipocytokines;adiponectin;leptin;resistin;visfatin;irisin;Hepatokines;angiopoietin like protein 2;hepatosscin;retinol binding protein 4;treatment like pioglitazone;liraglutide;elafibranor CVC(cerviciroc);obeticholic acid;aramchol;selonosertib;simtuzumab;Oxidative stress(OS);insulin resistance(IR)from 1980’s to 2021 till date.We found a total of 1050 articles out of which we selected 236 articles for this review.No meta-analysis was done.Hence diagnosis avoidance in addition to treatment of the generation as well as propagation of NAFLD/NASH are significant areas needing tackling.Thus here we have summarized the EP of NAFLD/NASH,as well as NAFLD/NASH,obtained HCC along with the present advantageous therapies under trial,for NAFLD/NASH.Moreover how adipocyte obtained adipokines along with liver obtained hepatokines might work as both diagnostic in addition to therapeutic targets from NAFLD to HCC.

Emerging Evidence Linking the Liver to the Cardiovascular System: Liver-derived Secretory Factors

Cardiovascular diseases(CVDs)remain the leading cause of morbidity and mortality worldwide.Recently,accumulating evidence has revealed hepatic mediators,termed as liverderived secretory factors(LDSFs),play an important role in regulating CVDs such as atherosclerosis,coronary artery disease,thrombosis,myocardial infarction,heart failure,metabolic cardiomyopathy,arterial hypertension,and pulmonary hypertension.LDSFs presented here consisted of microbial metabolite,extracellular vesicles,proteins,and microRNA,they are primarily or exclusively synthesized and released by the liver,and have been shown to exert pleiotropic actions on cardiovascular system.LDSFs mainly target vascular endothelial cell,vascular smooth muscle cells,cardiomyocytes,fibroblasts,macrophages and platelets,and further modulate endothelial nitric oxide synthase/nitric oxide,endothelial function,energy metabolism,inflammation,oxidative stress,and dystrophic calcification.Although some LDSFs are known to be detrimental/beneficial,controversial findings were also reported for many.Therefore,more studies are required to further explore the causal relationships between LDSFs and CVDs and uncover the exact mechanisms,which is expected to extend our understanding of the crosstalk between the liver and cardiovascular system and identify potential therapeutic targets.Furthermore,in the case of patients with liver disease,awareness should be given to the implications of these abnormalities in the cardiovascular system.These studies also underline the importance of early recognition and intervention of liver abnormalities in the practice of cardiovascular care,and a multidisciplinary approach combining hepatologists and cardiologists would be more preferable for such patients.

Type 2 diabetes originated from non-alcoholic fatty liver disease

Both non-alcoholic fatty liver disease(NAFLD)and type 2 diabetes mellitus(T2DM)are highly prevalent metabolic liver diseases.Accumulating epidemiological evidence now indicates that NAFLD and T2DM are strongly associated,yet the causative relationship remains to be elucidated.Liver serves as a hub for nutrient and energy metabolism in the body.Here we demonstrated the pathogenesis linking NAFLD to T2DM through a series of studies and the attenuation of T2DM progression after NALFD improvement in cohort study.We proposed the urgent necessity of NAFLD management and NAFLD drug development,which might be novel therapeutic avenues for T2DM.