obesity significantly increases the risk of cardiometabolic diseases , such as type 2 diabetes , dyslipidemia , hypertension , coronary heart disease , and stroke .
furthermore , recent evidence has shown that obesity is a risk factor for nonalcoholic fatty liver disease ( nafld ) , obstructive sleep apnea , dementia , and several types of cancers .
the main known function of adipose tissue is to store excess calories in the form of triglycerides and to release them during fasting and cold exposure .
moreover , adipose tissue has been established to be an endocrine organ that secretes adipokines , which are bioactive peptides that control systemic metabolism and energy homeostasis .
organokines , which are predominantly produced and se - creted by their respective tissues , affect whole body metabolism through autocrine , paracrine , and endocrine activities ( fig .
autologous to adipokines , myokines from skeletal muscle and hepatokines from the liver also regulate a variety of biological processes and communicate with distant target organs .
in obese individuals , the hypertrophy of adipocytes predisposes to immune cell infiltration , which produces proinflammatory cytokines , including interleukin 6 ( il-6 ) , il-8 , and monocyte chemoattractant protein-1 ( mcp-1 ) . with increasing body weight , individuals develop adipocyte hypertrophy , hypoxia , and ectopic fat deposition , which induces the altered production and secretion of adipokines in adipose tissue . adipose tissue dysfunction and disturbed adipokine secretion may connect obesity with its metabolic , inflammatory , and cardiovascular complications .
adipokines such as leptin , adiponectin , tumor necrosis factor  ( tnf- ) , retinol binding protein 4 ( rbp4 ) , adipocyte fatty acid binding protein ( a - fabp ) , resistin , vaspin , apelin , chemerin , omentin , and c1q / tnf - related proteins ( ctrps ) are involved in a spectrum of obesity - associated disorders .
in fact , several adipokines , such as leptin , rbp4 , il-6 , chemerin , and progranulin , are differentially expressed according to fat deposition .
leptin has a pivotal role in the regulation of appetite , satiety , food intake , energy expenditure , reproductive function , and fertility . in the hypothalamus
, leptin decreases orexigenic- and increases anorexigenic - neuropeptide synthesis , resulting in reduced appetite and body weight in animal experiments .
circulating leptin levels are proportional to body fat mass , and treatment with recombinant leptin shows only small effects on weight loss in humans .
adiponectin is a 30-kda protein which signals via at least two adiponectin receptors , adipor1 and adipor2 .
post - translational modification of adiponectin results in 180-kda hexamers ( low molecular weight ) and 18- to 36-mers ( high molecular weight ) .
adiponectin improves insulin sensitivity and has anti - diabetic , anti - inflammatory , and anti - atherogenic properties .
circulating adiponectin levels are inversely associated with components of the metabolic syndrome , including body weight , blood pressure , lipids , and insulin resistance .
furthermore , adiponectin levels show a negative relationship with visceral fat , type 2 diabetes , and cardiovascular disease ( cvd ) . we reported that circulating adiponectin levels showed a significant negative correlation with the mean target - to - background ratio , which reflects vascular inflammation using f - fluorodeoxyglucose positron emission tomography ( fdg - pet ) .
a - fabp is a novel adipokine that plays a key role in linking obesity with various features of metabolic syndrome , type 2 diabetes , and cvd . in macrophages , a - fabp potentiates toxic lipid - induced inflammation and endoplasmic reticulum ( er ) stress , which may be involved in the pathogenesis of cvd .
several prospective studies have shown that high a - fbap concentrations at baseline are predictive of the risk for metabolic and vascular morbidity , as well as mortality . in our previous study ,
a - fabp levels predicted the development of metabolic syndrome independent of traditional risk factors in korean children .
recent studies have shown that the ctrp family of proteins , paralogs of adiponectin , play a crucial role in the regulation of systemic metabolism and innate immunity . ctrp-1 to ctrp-15 show remarkable similarities in their structural and biochemical properties compared to adiponectin .
we observed that ctrp-3 concentrations are elevated in patients with dysregulation of glucose metabolism and are associated with various metabolic risk factors .
moreover , a 3-month combined exercise program significantly affected ctpr-3 and ctrp-5 levels in obese korean women .
patients with acute coronary syndrome and stable angina pectoris had significantly lower circulating ctrp-3 levels compared to control subjects .
recently , we demonstrated that ctrp9 attenuates hepatic steatosis through the alleviation of er stress via the amp - activated protein kinase ( ampk)-mediated induction of autophagy .
aging and physical inactivity result in a progressive loss of muscle mass and strength , known as sarcopenia .
we have previously studied the prevalence of sarcopenia and its impact on metabolic disorders , including type 2 diabetes and nafld .
regular exercise is an effective way to prevent and treat chronic metabolic disorders such as type 2 diabetes and metabolic syndrome .
myokines , proteins that are released from skeletal muscle , may mediate the beneficial effects of regular physical activity .
in fact , exercise affects the expression in skeletal muscle and the circulating levels of a number of myokines , such as il-6 , il-15 , angiopoietin - like 4 , myostatin , and irisin .
pedersen 's group first demonstrated that il-6 mrna expression in muscle , as well as circulating levels of il-6 , were markedly increased after exercise . during acute exercise
, il-6 improves insulin sensitivity by blocking proinflammatory signaling pathways in the muscle . however , chronically elevated il-6 induces insulin resistance in adipose tissue and the liver .
irisin is an exercise - induced novel myokine that promotes the browning of white adipose tissue and may mediate the health - promoting effects of exercise , including improvement in glycemic control . however , controversy has arisen regarding inconsistencies in the regulation of irisin after exercise . we showed that circulating irisin concentrations were not different in individuals with sarcopenia and those with brown adipose tissue detectable by fdg - pet .
liver - derived proteins known as hepatokines have recently emerged as novel hormones that have ambivalent roles , either aggravating insulin resistance or improving metabolic variables in the metabolic syndrome .
fetuin - a is the first - known hepatokine that integrates crosstalk between the liver and target organs .
fetuin - a , a natural inhibitor of the insulin - stimulated insulin receptor tyrosine kinase , induces insulin resistance in rodents .
fetuin - a was identified as an endogenous ligand for toll - like receptor 4 through which saturated fatty acids induce proinflammatory signaling and insulin resistance .
circulating fetuin - a levels are increased in obesity , metabolic syndrome , and type 2 diabetes , and are correlated with hepatic steatosis in humans . furthermore , prospective studies have shown that fetuin - a levels predict the increased risk of type 2 diabetes as well as myocardial infarction and stroke .
we reported that adiponectin and salsalate improve hepatic steatosis by the inhibition of fetuin - a through the ampk - nuclear factor-b pathway .
furthermore , we found that caloric restriction significantly decreased hepatic fetuin - a expression and its circulating levels in obese rats and humans with type 2 diabetes .
fibroblast growth factor 21 ( fgf21 ) is a central metabolic regulator that has favorable effects on glucose and lipid metabolism .
fgf21 is upregulated by the nuclear receptor peroxisome proliferator - activated receptor  during starvation .
administration of fgf21 has been shown to decrease body weight , blood glucose , and lipid levels , as well as improves insulin resistance in animal experiments .
fgf21 decreases blood glucose levels by increasing glucose transporter 1 expression in human primary adipocytes and reduces triglyceride levels by inhibiting lipolysis and augmenting -oxidation in the liver and adipose tissue .
circulating concentrations and the hepatic expression of fgf21 are increased in patients with nafld . in a recent randomized clinical trial , treatment with ly2405319 ,
an analog of fgf21 , resulted in significant improvements in the dyslipidemia of obese human subjects with type 2 diabetes .
selenoprotein p is positively correlated with insulin resistance and is upregulated in patients with type 2 diabetes . in our previous study ,
selenoprotein p levels were elevated in patients with dysregulated glucose metabolism and were significantly associated with insulin resistance , inflammation , and carotid intima - media thickness .
we also reported that ampk activators alleviate carrageenan - induced insulin resistance through the ampk - mediated amelioration of er stress in hepatocytes . circulating selenoprotein p levels
are negatively correlated with adiponectin levels in patients with type 2 diabetes , suggesting the existence of crosstalk between a hepatokine ( selenoprotein p ) and an adipokine ( adiponectin ) .
altered adipokine production and secretion may provide a link between adipose tissue dysfunction and obesity - related disorders .
adipokines are pivotal regulators in whole body metabolism because they are involved in impaired insulin sensitivity or secretion , inflammation , fat distribution , appetite , and satiety , as well as endothelial dysfunction and atherosclerosis .
analogous to the role of adipokines , myokines and hepatokines have also been proven to have crucial pathogenic roles in metabolic syndrome , nafld , type 2 diabetes , and cvd .
the identification and functional characterization of novel organokines may provide important insights that could lead to novel treatments for cardiometabolic diseases .
 immoderate energy intake , a sedentary lifestyle , and aging have contributed to the increased prevalence of obesity , sarcopenia , metabolic syndrome , type 2 diabetes , and cardiovascular disease . 
 there is an urgent need for the development of novel pharmacological interventions that can target excessive fat accumulation and decreased muscle mass and/or strength . 
 adipokines , bioactive molecules derived from adipose tissue , are involved in the regulation of appetite and satiety , inflammation , energy expenditure , insulin resistance and secretion , glucose and lipid metabolism , and atherosclerosis . 
 recently , there is emerging evidence that skeletal muscle and the liver also function as endocrine organs that secrete myokines and hepatokines , respectively . 
 novel discoveries and research into these organokines ( adipokines , myokines , and hepatokines ) may lead to the development of promising biomarkers and therapeutics for cardiometabolic disease . in this review , 
 i summarize recent data on these organokines and focus on the role of adipokines , myokines , and hepatokines in the regulation of insulin resistance , inflammation , and atherosclerosis . 
INTRODUCTION
ADIPOKINES
MYOKINES
HEPATOKINES
CONCLUSIONS