Hepatokines and metabolism: Deciphering communication from the liver

In the paper

“Leukocyte cell-derived chemotaxin 2 (LECT2) is an energy-sensing hepatokine that is positively associated with hepatic inflammatory signaling, obesity, NAFLD, and insulin resistance [239,240].”

What the sources say

• Partly supported

  The Abstract (p. 3) identifies LECT2 as an energy-sensing hepatokine and reports positive correlations with obesity and insulin resistance in humans. The paper does not establish a positive association with NAFLD: it reports mild steatosis alongside increased liver Lect2 expression in high-fat-fed mice (p. 17). Nor does it establish a positive association with hepatic inflammatory signaling; the Discussion (p. 26) instead describes context-dependent inflammatory effects, including attenuation of liver inflammation. (LLM, conf=0.88)

  cites [239] Lan, 2014, LECT2 functions as a hepatokine that links obesity to skeletal muscle insulin resistance, Diabetes sourceExperimental — accuracy not yet measured
• Partly supported

  The LECT2 section (page unavailable) calls LECT2 an energy-sensing hepatokine and reports positive relationships with BMI and insulin resistance, plus elevated levels in obesity and fatty liver. It does not establish a positive association specifically with hepatic inflammatory signaling: the reported induction of proinflammatory cytokines is in human endothelial cells, while involvement in hepatitis is hedged as a possibility. (LLM, conf=0.85)

  cites [240] Jung, 2016, Implication of hepatokines in metabolic disorders and cardiovascular diseases, BBA Clin sourceExperimental — accuracy not yet measured

In the paper

“The liver can sense and respond to nutrient overabundance and deficit by secreting hepatokines, which signal energy status and help regulate nutrient availability to multiple peripheral tissues and the central nervous system (CNS).”

In the paper

“In response to fasting, however, the liver increases hepatic glucose production via glycogenolysis and gluconeogenesis to supply glucose as a fuel source for non-hepatic tissues including the brain and skeletal muscle [15,16].”

What the sources say

• Not checked yetcites [15] Roden, 2003, Hepatic glucose metabolism in humans—its role in health and disease, Best Practice & Research Clinical Endocrinology & Metabolism source
• Not checked yetcites [16] Leone, 1999, A critical role for the peroxisome proliferator-activated receptor alpha (PPARalpha) in the cellular fasting response: the PPARalpha-null mouse as a model of fatty acid oxidation disorders, Proceedings of the National Academy of Sciences of the U S A source

In the paper

“NAFLD is the most common chronic liver disease worldwide and a risk factor for type 2 diabetes, obesity, and cardiovascular disease (CVD) [8,12,22].”

What the sources say

• Not checked yetcites [8] Iroz, 2015, Hepatokines: unlocking the multi-organ network in metabolic diseases, Diabetologia source
• Not checked yetcites [12] Stefan, 2013, The role of hepatokines in metabolism, Nature Reviews Endocrinology source
• Not checked yetcites [22] Morrison, 2019, Causality between non-alcoholic fatty liver disease and risk of cardiovascular disease and type 2 diabetes: a meta-analysis with bias analysis, Liver International source

In the paper

“ANGPTL3 is exclusively expressed and secreted by the liver and has emerged as an important regulator of plasma triglyceride levels due to its inhibition of LPL in oxidative tissues [34] (Figure 3).”

What the sources say

• Not checked yetcites [34] Conklin, 1999, Identification of a mammalian angiopoietin-related protein expressed specifically in liver, Genomics source

In the paper

“Activin-E expression increases during fasting and is markedly suppressed by loss of the insulin receptor in the liver [10], suggesting dynamic regulation.”

What the sources say

• Not checked yetcites [10] Smati, 2020, Regulation of hepatokine gene expression in response to fasting and feeding: influence of PPAR-alpha and insulin-dependent signalling in hepatocytes, Diabetes & Metabolism source

In the paper

“Furthermore, circulating levels of activin-E are elevated in high-fat diet-fed mice and are thought to contribute to resistance to body weight gain [28,30].”

What the sources say

• Not checked yetcites [28] Chabicovsky, 2003, Overexpression of activin beta(C) or activin beta(E) in the mouse liver inhibits regenerative deoxyribonucleic acid synthesis of hepatic cells, Endocrinology source
• Not checked yetcites [30] Hashimoto, 2018, Activin E controls energy homeostasis in both Brown and white adipose tissues as a hepatokine, Cell Reports source

In the paper

“Insulin resistance occurs when insulin is unable to properly (1) stimulate glucose uptake into metabolic tissues (skeletal muscle and adipose tissues), (2) suppress hepatic glucose production, and/or (3) reduce adipose tissue lipolysis [17].”

What the sources say

• Not checked yetcites [17] Hotamisligil, 2006, Inflammation and metabolic disorders, Nature source

In the paper

“Dysregulation of liver-centered inter-organ pathways may contribute to improper regulation of energy homeostasis and ultimately metabolic dysfunction.”

In the paper

“During hepatic insulin resistance, excess storage of ectopic fat in the liver can contribute to the development of non-alcoholic fatty liver disease (NAFLD) [[17], [18], [19], [20]].”

What the sources say

• Not checked yetcites [17], [18], [19], [20]

In the paper

“The liver regulates systemic glucose homeostasis through hepatic glucose production and glycogen storage.”

In the paper

“The liver has recently been recognized as an endocrine organ that secretes hepatokines, which are liver-derived factors that can signal to and communicate with distant tissues.”

In the paper

“FGF21, unlike traditional FGFs, is an endocrine hormone produced and secreted predominantly by the liver [129,130].”

What the sources say

• Not checked yetcites [129] Nishimura, 2000, Identification of a novel FGF, FGF-21, preferentially expressed in the liver, Biochimica et Biophysica Acta source
• Not checked yetcites [130] Fon Tacer, 2010, Research resource: comprehensive expression atlas of the fibroblast growth factor system in adult mouse, Molecular Endocrinology source

In the paper

“FST acts as a multi-faceted hepatokine that is involved in reproduction [181], muscle growth [182], cancer development [183], and metabolism [184].”

What the sources say

• Not checked yetcites [181] de Kretser, 2002, Inhibins, activins and follistatin in reproduction, Human Reproduction Update source
• Not checked yetcites [182] Rodino-Klapac, 2009, Inhibition of myostatin with emphasis on follistatin as a therapy for muscle disease, Muscle & Nerve source
• Not checked yetcites [183] Shi, 2016, Clinical and therapeutic implications of follistatin in solid tumours, CANCER GENOMICS and PROTEOMICS source

In the paper

“Most of FST's effects on reproductive health and cancer development are related to its interactions with activins and follicle-stimulating hormone, while its effects on muscle growth result from interactions with myostatin [186].”

What the sources say

• Not checked yetcites [186] Brown, 2011, Follistatin and follistatin like-3 differentially regulate adiposity and glucose homeostasis, Obesity source

In the paper

“Under fasted conditions, FGF21 increases hepatic gluconeogenesis, β-oxidation, and ketogenesis in mice [142,154].”

What the sources say

• Not checked yetcites [142] Hotta, 2009, Fibroblast growth factor 21 regulates lipolysis in white adipose tissue but is not required for ketogenesis and triglyceride clearance in liver, Endocrinology source
• Not checked yetcites [154] Potthoff, 2009, FGF21 induces PGC-1alpha and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response, Proceedings of the National Academy of Sciences of the U S A source

In the paper

“FGF21 signaling to the ventromedial hypothalamus (VMH) is required for its effects on lowering carbohydrate intake but not non-nutritive sweet-taste preference or body weight.”

What the sources say

• Not checked yetcites [173] Jensen-Cody, 2020, FGF21 signals to glutamatergic neurons in the ventromedial hypothalamus to suppress carbohydrate intake, Cell Metabolism source

In the paper

“FGF21 expression is regulated by nutrient signals and subsequently functions to regulate nutrient homeostasis.”

In the paper

“Administration of FGF21 analogs to obese and type 2 diabetic subjects improves dyslipidemia, decreases body weight, improves fasting insulin levels, and was recently thoroughly reviewed [136] (Figure 2).”

What the sources say

• Not checked yetcites [136] Gaich, 2013, The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes, Cell Metabolism source

In the paper

“This robust increase in FGF21 results in increased energy expenditure and lower body weight gain [155,156,160,163] (Figure 2)”

What the sources say

• Not checked yetcites [155] Laeger, 2014, FGF21 is an endocrine signal of protein restriction, Journal of Clinical Investigation source
• Not checked yetcites [156] Maida, 2016, A liver stress-endocrine nexus promotes metabolic integrity during dietary protein dilution, Journal of Clinical Investigation source
• Not checked yetcites [160] Pérez-Martí, 2017, A low-protein diet induces body weight loss and browning of subcutaneous white adipose tissue through enhanced expression of hepatic fibroblast growth factor 21 (FGF21), Molecular Nutrition & Food Research source
• Not checked yetcites [163] Flippo, 2020, FGF21 signaling in glutamatergic neurons is required for weight loss associated with dietary protein dilution, Scientific Reports source

In the paper

“while it signals the CNS to increase energy expenditure and decrease body weight [169,171,172] (Figure 2).”

What the sources say

• Not checked yetcites [169] BonDurant, 2017, FGF21 regulates metabolism through adipose-dependent and -independent mechanisms, Cell Metabolism source
• Not checked yetcites [171] Ameka, 2019, Liver derived FGF21 maintains core body temperature during acute cold exposure, Scientific Reports source
• Not checked yetcites [172] Owen, 2014, FGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss, Cell Metabolism source

In the paper

“In humans, circulating FGF21 levels also increase with obesity [[174], [175], [176]], type 2 diabetes [[176], [177], [178]], and NAFLD [179,180]”

What the sources say

• Not checked yetcites [174] Zhang, 2008, Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans, Diabetes source
• Not checked yetcites [175] Berti, 2015, Fibroblast growth factor 21 is elevated in metabolically unhealthy obesity and affects lipid deposition, adipogenesis, and adipokine secretion of human abdominal subcutaneous adipocytes, Mol Metab source
• Not checked yetcites [176] Mraz, 2009, Serum concentrations and tissue expression of a novel endocrine regulator fibroblast growth factor-21 in patients with type 2 diabetes and obesity, Clinical Endocrinology source

In the paper

“Classically recognized as a fasting hormone regulated by the nuclear receptor peroxisome proliferator-activated receptor α (PPARα) [150,151]”

What the sources say

• Not checked yetcites [150] Badman, 2007, Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states, Cell Metabolism source
• Not checked yetcites [151] Inagaki, 2007, Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21, Cell Metabolism source

In the paper

“FST acts as an inhibitor of members of the TGF-β superfamily, including myostatin and activins [185,186], and can function as a promoter of skeletal muscle growth [187].”

What the sources say

• Not checked yetcites [185] Sidis, 2006, Biological activity of follistatin isoforms and follistatin-like-3 is dependent on differential cell surface binding and specificity for activin, myostatin, and bone morphogenetic proteins, Endocrinology source
• Not checked yetcites [186] Brown, 2011, Follistatin and follistatin like-3 differentially regulate adiposity and glucose homeostasis, Obesity source
• Not checked yetcites [187] Lee, 2010, Regulation of muscle mass by follistatin and activins, Molecular Endocrinology source

In the paper

“FST is secreted by a broad range of cell types, and plasma levels are thought to result from paracrine/autocrine signaling spillover [188].”

What the sources say

• Not checked yetcites [188] Hansen, 2016, Circulating follistatin in relation to energy metabolism, Molecular and Cellular Endocrinology source

In the paper

“Administration of hGDF15 to GFRAL-deficient mice had no effect on body weight, energy expenditure, serum leptin and insulin levels, and food intake compared to wild-type mice given hGDF15 [213].”

What the sources say

• Not checked yetcites [213] Yang, 2017, GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand, Natura Med source

In the paper

“Patients with type 2 diabetes have slightly elevated levels of circulating FST and plasma levels associated with glycemic parameters in these patients [188,191,192] (Table 1).”

What the sources say

• Not checked yetcites [188] Hansen, 2016, Circulating follistatin in relation to energy metabolism, Molecular and Cellular Endocrinology source
• Not checked yetcites [191] Hansen, 2013, Plasma follistatin is elevated in patients with type 2 diabetes: relationship to hyperglycemia, hyperinsulinemia, and systemic low-grade inflammation, Diabetes Metab Res Rev source
• Not checked yetcites [192] Hansen, 2016, Exercise-induced secretion of FGF21 and follistatin are blocked by pancreatic clamp and impaired in type 2 diabetes, Journal of Clinical Endocrinology & Metabolism source

In the paper

“Hepassocin has mitogenic activity on hepatocytes, serving as a regulator of hepatic growth and proliferation [218].”

What the sources say

• Not checked yetcites [218] Gao, 2014, Hepassocin activates the EGFR/ERK cascade and induces proliferation of L02 cells through the Src-dependent pathway, Cellular Signalling source

In the paper

“FST functions to increase the phosphorylation of MAPK/ERK1/2 proteins in WAT and increase the expression of Myf5 protein in BAT, which increases UCP1 expression in both tissues [198].”

What the sources say

• Not checked yetcites [198] Singh, 2017, Follistatin targets distinct pathways to promote Brown adipocyte characteristics in Brown and white adipose tissues, Endocrinology source

In the paper

“GDF15 binds with high affinity to GFRAL and its co-receptor RET, which induces phosphorylation of RET, leading to downstream signaling through the AKT, ERK1/2, and phospholipase C (PLCγ) pathways [201,213,215].”

What the sources say

• Not checked yetcites [201] Mullican, 2018, Uniting GDF15 and GFRAL: therapeutic opportunities in obesity and beyond, Trends in Endocrinology and Metabolism source
• Not checked yetcites [213] Yang, 2017, GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand, Natura Med source
• Not checked yetcites [215] Hsu, 2017, Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15, Nature source

In the paper

“This discrepancy may have been due to differences in the mode and duration of elevated GDF15 levels.”

In the paper

“Plasma levels of hepassocin are associated with fasted plasma glucose, HOMA-IR, and prediabetes and increase in patients with type 2 diabetes (Table 1) [217,220].”

What the sources say

• Not checked yetcites [217] Wu, 2016, A novel hepatokine, HFREP1, plays a crucial role in the development of insulin resistance and type 2 diabetes, Diabetologia source
• Not checked yetcites [220] Huang, 2020, Discovery of a role of the novel hepatokine, hepassocin, in obesity, BioFactors source

In the paper

“FST is present in three main isoforms, FST288, FST303, and FST315, with FST315 being the predominant isoform found in the circulation [185,194,195].”

What the sources say

• Not checked yetcites [185] Sidis, 2006, Biological activity of follistatin isoforms and follistatin-like-3 is dependent on differential cell surface binding and specificity for activin, myostatin, and bone morphogenetic proteins, Endocrinology source
• Not checked yetcites [194] Shimasaki, 1988, Primary structure of the human follistatin precursor and its genomic organization, Proceedings of the National Academy of Sciences of the U S A source
• Not checked yetcites [195] Schneyer, 2004, Differential distribution of follistatin isoforms: application of a new FS315-specific immunoassay, Journal of Clinical Endocrinology & Metabolism source

In the paper

“The expression of human GDF15 (hGDF15) improved glucose tolerance and insulin sensitivity, lowered body weight and leptin levels, and increased oxidative metabolism and energy expenditure in mice [207,208] (Figure 2).”

What the sources say

• Not checked yetcites [207] Baek, 2006, Nonsteroidal anti-inflammatory drug-activated gene-1 over expression in transgenic mice suppresses intestinal neoplasia, Gastroenterology source
• Not checked yetcites [208] Chrysovergis, 2014, NAG-1/GDF-15 prevents obesity by increasing thermogenesis, lipolysis and oxidative metabolism, International Journal of Obesity source

In the paper

“Hepassocin is secreted predominantly from the liver, but is also expressed in adipose tissue where it is suggested to regulate lipid metabolism [219].”

What the sources say

• Not checked yetcites [219] Demchev, 2013, Targeted deletion of fibrinogen like protein 1 reveals a novel role in energy substrate utilization, PloS One source

In the paper

“GFRAL is exclusively expressed in the human brainstem and is responsible for the metabolic effects of GDF15 on regulating appetite [201,215].”

What the sources say

• Not checked yetcites [201] Mullican, 2018, Uniting GDF15 and GFRAL: therapeutic opportunities in obesity and beyond, Trends in Endocrinology and Metabolism source
• Not checked yetcites [215] Hsu, 2017, Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15, Nature source

In the paper

“Conversely, administration of GDF15 to wild-type mice produced responses similar to those in transgenic mice; however, these mice exhibited consistent reduction in food intake [201,213].”

What the sources say

• Not checked yetcites [201] Mullican, 2018, Uniting GDF15 and GFRAL: therapeutic opportunities in obesity and beyond, Trends in Endocrinology and Metabolism source
• Not checked yetcites [213] Yang, 2017, GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand, Natura Med source

In the paper

“A recent study found that GDF15 induced anorexia through nausea and emesis in mice and musk shrews, respectively [216].”

What the sources say

• Not checked yetcites [216] Borner, 2020, GDF15 induces anorexia through nausea and emesis, Cell Metabolism source

In the paper

“Growth differentiation factor 15 (GDF15), also called macrophage inhibitory cytokine-1, is associated with numerous biological processes and diseases including cancer, cardiovascular disease, and obesity [[199], [200], [201], [202]].”

What the sources say

• Not checked yetcites [199] Bauskin, 2006, Role of macrophage inhibitory cytokine-1 in tumorigenesis and diagnosis of cancer, Cancer Research source
• Not checked yetcites [200] Breit, 2011, The TGF-β superfamily cytokine, MIC-1/GDF15: a pleotrophic cytokine with roles in inflammation, cancer and metabolism, Growth Factors source
• Not checked yetcites [201] Mullican, 2018, Uniting GDF15 and GFRAL: therapeutic opportunities in obesity and beyond, Trends in Endocrinology and Metabolism source

In the paper

“GDF15 belongs to the TGF-β superfamily and is upregulated by several inflammatory or stress-related proteins, including interleukin (IL)-1β, IL-2, and tumor necrosis factor (TNF) alpha.”

In the paper

“Physiological levels of circulating GDF15 are low in healthy humans but increase in disease states and during pregnancy [203] (Table 1).”

What the sources say

• Not checked yetcites [203] Li, 2000, Placental transforming growth factor-beta is a downstream mediator of the growth arrest and apoptotic response of tumor cells to DNA damage and p53 overexpression, Journal of Biological Chemistry source

In the paper

“Two studies found that GDF15 transgenic mice were protected against obesity and had increased insulin sensitivity and energy expenditure without any changes in food consumption compared to control mice [207,208].”

What the sources say

• Not checked yetcites [207] Baek, 2006, Nonsteroidal anti-inflammatory drug-activated gene-1 over expression in transgenic mice suppresses intestinal neoplasia, Gastroenterology source
• Not checked yetcites [208] Chrysovergis, 2014, NAG-1/GDF-15 prevents obesity by increasing thermogenesis, lipolysis and oxidative metabolism, International Journal of Obesity source

In the paper

“While GDF15 is not highly expressed in the human liver under basal conditions, it is highly expressed in the liver, adipose, and intestine in mice [[204], [205], [206]].”

What the sources say

• Not checked yetcites [204] Hsiao, 2000, Characterization of growth-differentiation factor 15, a transforming growth factor beta superfamily member induced following liver injury, Molecular and Cellular Biology source
• Not checked yetcites [205] Baek, 2019, Growth differentiation factor 15 (GDF15): a survival protein with therapeutic potential in metabolic diseases, Pharmacology & Therapeutics source
• Not checked yetcites [206] Lockhart, 2020, GDF15: a hormone conveying somatic distress to the brain, Endocrine Reviews source

In the paper

“Overexpression of FST in mice resulted in insulin resistance in WAT, increased hepatic glucose production, and impaired whole-body glucose tolerance, consistent with higher expression in patients with type 2 diabetes [77,196].”

What the sources say

• Not checked yetcites [77] Gonzalez-Gil, 2020, The role of exercise in the interplay between myokines, hepatokines, osteokines, adipokines, and modulation of inflammation for energy substrate redistribution and fat mass loss: a review, Nutrients source
• Not checked yetcites [196] Tao, 2018, Inactivating hepatic follistatin alleviates hyperglycemia, Natura Med source

In the paper

“LECT2-deficient mice exhibited increased glucose tolerance and insulin sensitivity [239].”

What the sources say

• Not checked yetcites [239] Lan, 2014, LECT2 functions as a hepatokine that links obesity to skeletal muscle insulin resistance, Diabetes source

In the paper

“While IGF2 functions predominantly in early embryogenesis [226]”

What the sources say

• Not checked yetcites [226] Baker, 1993, Role of insulin-like growth factors in embryonic and postnatal growth, Cell source

In the paper

“LCN13 in particular is secreted from multiple tissues including the liver to regulate glucose homeostasis and improve insulin sensitivity [254].”

What the sources say

• Not checked yetcites [254] Zhou, 2013, Lipocalin 13 regulation of glucose and lipid metabolism in obesity, Vitamins & Hormones source

In the paper

“Administration of recombinant hepassocin or hepatic overexpression of hepassocin in mice induces insulin resistance in the liver and skeletal muscle, while loss of hepassocin improves high-fat diet-induced insulin resistance in wild-type and ob/ob mice [217] (Figure 3).”

What the sources say

• Not checked yetcites [217] Wu, 2016, A novel hepatokine, HFREP1, plays a crucial role in the development of insulin resistance and type 2 diabetes, Diabetologia source

In the paper

“Decreased expression of LECT2 is observed during tissue inflammation, fibrosis, or pathology, suggesting that LECT2 functions positively under normal conditions.”

In the paper

“These mice also exhibited increased insulin-stimulated AKT phosphorylation in skeletal muscle but not in the liver or adipose tissue, suggesting that loss of LECT2 selectively improves insulin sensitivity in skeletal muscle [239].”

What the sources say

• Not checked yetcites [239] Lan, 2014, LECT2 functions as a hepatokine that links obesity to skeletal muscle insulin resistance, Diabetes source

In the paper

“For example, mice that were fed high-fat diets or exercised had increased or decreased serum and hepatic levels of LECT2, respectively [239].”

What the sources say

• Not checked yetcites [239] Lan, 2014, LECT2 functions as a hepatokine that links obesity to skeletal muscle insulin resistance, Diabetes source

In the paper

“Lipocalin (LCN) proteins are secreted proteins that bind small hydrophobic ligands through their conical β barrels [252,253].”

What the sources say

• Not checked yetcites [252] Grzyb, 2006, Lipocalins - a family portrait, Journal of Plant Physiology source
• Not checked yetcites [253] Flower, 1996, The lipocalin protein family: structure and function, Biochemical Journal source

In the paper

“Insulin-like growth factors (IGFs) are structurally and functionally related to insulin and play an important role in enhancing insulin sensitivity [222].”

What the sources say

• Not checked yetcites [222] Moses, 1996, Recombinant human insulin-like growth factor I increases insulin sensitivity and improves glycemic control in type II diabetes, Diabetes source

In the paper

“IGF1 is secreted into the circulation by the liver in response to growth hormone stimulation [227].”

What the sources say

• Not checked yetcites [227] Van Wyk, 1999, Insulin-like growth factors and skeletal growth: possibilities for therapeutic interventions, Journal of Clinical Endocrinology & Metabolism source

In the paper

“IGFs are regulated by a family of IGF-binding proteins (IGFBP) that can bind IGFs with equal or greater affinity than IGF1R [224,225].”

What the sources say

• Not checked yetcites [224] Rajkumar, 1996, Impaired glucose homeostasis in insulin-like growth factor binding protein-1 transgenic mice, Journal of Clinical Investigation source
• Not checked yetcites [225] Jones, 1995, Insulin-like growth factors and their binding proteins: biological actions∗, Endocrine Reviews

In the paper

“There is evidence that low plasma levels of IGF1 predict the development of type 2 diabetes and correlate with insulin resistance and increased risk of metabolic syndrome and cardiovascular disease [[231], [232], [233]] (Table 1).”

What the sources say

• Not checked yetcites [231] Sandhu, 2002, Circulating concentrations of insulin-like growth factor-I and development of glucose intolerance: a prospective observational study, The Lancet source
• Not checked yetcites [232] Succurro, 2009, Low plasma insulin-like growth factor-1 levels are associated with reduced insulin sensitivity and increased insulin secretion in nondiabetic subjects, Nutrition, Metabolism, and Cardiovascular Diseases source
• Not checked yetcites [233] Juul, 2002, Low serum insulin-like growth factor I is associated with increased risk of ischemic heart disease: a population-based case-control study, Circulation source

In the paper

“LECT2 functions in liver regeneration, immune modulation, bone growth, neural development, glucose metabolism, metabolic syndrome, and cancer [[241], [242], [243], [244], [245], [246]].”

What the sources say

• Not checked yetcites [241] Segawa, 2001, Possible changes in expression of chemotaxin LECT2 mRNA in mouse liver after concanavalin A-induced hepatic injury, Biological and Pharmaceutical Bulletin source
• Not checked yetcites [242] Yamagoe, 1996, Purification and primary amino acid sequence of a novel neutrophil chemotactic factor LECT2, Immunology Letters source
• Not checked yetcites [243] Ovejero, 2004, Identification of the leukocyte cell-derived chemotaxin 2 as a direct target gene of beta-catenin in the liver, Hepatology source

In the paper

“Administration of IGF1 in humans results in decreased blood glucose levels and improved insulin sensitivity in those with and without type 2 diabetes [[234], [235], [236]].”

What the sources say

• Not checked yetcites [234] Laron, 1995, Carbohydrate metabolism in primary growth hormone resistance (Laron syndrome) before and during insulin-like growth factor-I treatment, Metabolism source
• Not checked yetcites [235] Laron, 1999, The essential role of IGF-I: lessons from the long-term study and treatment of children and adults with Laron syndrome, Journal of Clinical Endocrinology & Metabolism source
• Not checked yetcites [236] Hong, 2017, Central IGF1 improves glucose tolerance and insulin sensitivity in mice, Nutrition & Diabetes source

In the paper

“IGFBP1 is elevated in patients with type 2 diabetes and has been shown to counteract the hypoglycemic effect of insulin through inhibition of IGF1 [224].”

What the sources say

• Not checked yetcites [224] Rajkumar, 1996, Impaired glucose homeostasis in insulin-like growth factor binding protein-1 transgenic mice, Journal of Clinical Investigation source

In the paper

“LECT2-deficient mice showed improved insulin sensitivity in skeletal muscle, while administration of recombinant LECT2 in mice led to impaired insulin signaling and induced insulin resistance in skeletal muscle [239] (Figure 3).”

What the sources say

• Not checked yetcites [239] Lan, 2014, LECT2 functions as a hepatokine that links obesity to skeletal muscle insulin resistance, Diabetes source

In the paper

“LECT2 alters insulin signaling through the JNK pathway in myocytes, and the expression of LECT2 in the liver is negatively regulated by the energy-depletion sensor AMPK [239,248,249].”

What the sources say

• Not checked yetcites [239] Lan, 2014, LECT2 functions as a hepatokine that links obesity to skeletal muscle insulin resistance, Diabetes source
• Not checked yetcites [248] Hwang, 2015, LECT2 induces atherosclerotic inflammatory reaction via CD209 receptor-mediated JNK phosphorylation in human endothelial cells, Metabolism source
• Not checked yetcites [249] Hwang, 2015, A dipeptidyl peptidase-IV inhibitor improves hepatic steatosis and insulin resistance by AMPK-dependent and JNK-dependent inhibition of LECT2 expression, Biochemical Pharmacology source

In the paper

“it is well established that LCN13 regulates glucose metabolism in adipocytes and hepatocytes by enhancing insulin signaling, insulin-stimulated glucose uptake, and insulin suppression of glucose production [254,258].”

What the sources say

• Not checked yetcites [254] Zhou, 2013, Lipocalin 13 regulation of glucose and lipid metabolism in obesity, Vitamins & Hormones source
• Not checked yetcites [258] Cho, 2011, Lipocalin-13 regulates glucose metabolism by both insulin-dependent and insulin-independent mechanisms, Molecular and Cellular Biology source

In the paper

“Liver injury in mice enhances the expression of hepassocin in adipose tissues, suggesting crosstalk between the liver and adipose tissue, although its role in obesity remains obscure [219].”

What the sources say

• Not checked yetcites [219] Demchev, 2013, Targeted deletion of fibrinogen like protein 1 reveals a novel role in energy substrate utilization, PloS One source

In the paper

“Altogether, it is clear that IGF1 plays an important role in maintaining insulin sensitivity; however, the full mechanism by which it does so has not been completely resolved.”

In the paper

“The two main IGFs, IGF1 and IGF2, bind the IGF1 receptor (IGF1R), which elicits phosphorylation of intracellular adaptor proteins and activation of MAPK and PI3K/AKT signaling pathways [223].”

What the sources say

• Not checked yetcites [223] Menu, 2004, Specific roles for the PI3K and the MEK-ERK pathway in IGF-1-stimulated chemotaxis, VEGF secretion and proliferation of multiple myeloma cells: study in the 5T33MM model, British Journal of Cancer source

In the paper

“Interestingly, tissues normally lacking LECT2 exhibit increased expression of LECT2 in disease settings, indicating that improper upregulation of LECT2 may contribute to pathological conditions [246,247].”

What the sources say

• Not checked yetcites [246] Slowik, 2017, Leukocyte cell-derived chemotaxin-2: it's role in pathophysiology and future in clinical medicine, Clin Transl Sci source
• Not checked yetcites [247] Nagai, 1998, Systemic expression of a newly recognized protein, LECT2, in the human body, Pathology International source

In the paper

“LECT2 is expressed in the liver, adipose tissue, neurons, and white blood cells and is often found in the circulation.”

In the paper

“Interestingly, there is a positive relationship between circulating LECT2 levels, BMI, and insulin resistance in humans [239] (Table 1).”

What the sources say

• Not checked yetcites [239] Lan, 2014, LECT2 functions as a hepatokine that links obesity to skeletal muscle insulin resistance, Diabetes source

In the paper

“IGFs promotes cell growth, proliferation, differentiation, and survival in an endocrine, paracrine, and autocrine fashion.”

In the paper

“Expression and secretion of LCN13 in mice vary in response to changes in metabolic states, suggesting a role for this hepatokine in nutrient sensing and regulation [254].”

What the sources say

• Not checked yetcites [254] Zhou, 2013, Lipocalin 13 regulation of glucose and lipid metabolism in obesity, Vitamins & Hormones source

In the paper

“Administration of a long-lasting SMOC1-Fc fusion protein improved glycemic control, cholesterol, and NAFLD activity scores in lean and obese mice up to 4 weeks following the final administration of SMOC1-Fc [266].”

What the sources say

• Not checked yetcites [266] Montgomery, 2020, SMOC1 is a glucose-responsive hepatokine and therapeutic target for glycemic control, Science Translational Medicine source

In the paper

“Selenoprotein P (SeP) is a glycoprotein that is secreted predominantly from the liver and is upregulated by selenium and glucose supplies but downregulated by insulin and adiponectin [260,261].”

What the sources say

• Not checked yetcites [260] Misu, 2010, A liver-derived secretory protein, selenoprotein P, causes insulin resistance, Cell Metabolism source
• Not checked yetcites [261] Misu, 2012, Inverse correlation between serum levels of selenoprotein P and adiponectin in patients with type 2 diabetes, PloS One source

In the paper

“Mice overexpressing LCN13 are resistant to high-fat diet-induced hepatic steatosis and hyperlipidemia [259].”

What the sources say

• Not checked yetcites [259] Sheng, 2011, Lipocalin 13 protein protects against hepatic steatosis by both inhibiting lipogenesis and stimulating fatty acid β-oxidation, Journal of Biological Chemistry source

In the paper

“The liver responds to energy influx and demand by secreting hepatokines that act on various tissues to facilitate energy utilization or storage.”

In the paper

“These hepatokines can act in isolation or in conjunction with other factors to coordinate systemic metabolic processes.”

In the paper

“Tsukushi (TSK) is an inducible hepatokine that regulates energy expenditure and is strongly associated with NAFLD, NASH, and obesity [269,270].”

What the sources say

• Not checked yetcites [269] Mouchiroud, 2019, The hepatokine Tsukushi is released in response to NAFLD and impacts cholesterol homeostasis, JCI Insight source
• Not checked yetcites [270] Xiong, 2019, Mapping the molecular signatures of diet-induced NASH and its regulation by the hepatokine Tsukushi, Mol Metab source

In the paper

“Interestingly, SMOC1 has no effect on food intake, body weight, or energy expenditure.”

In the paper

“TSK-deficient mice were resistant to diet-induced obesity, insulin resistance, and hepatic steatosis as a result of enhanced sympathetic activation and brown fat thermogenesis [271].”

What the sources say

• Not checked yetcites [271] Wang, 2019, The hepatokine Tsukushi gates energy expenditure via brown fat sympathetic innervation, Nat Metab source

In the paper

“LCN13 likely regulates lipid metabolism by downregulating the expression of key liver lipogenic genes including ChREBP and PPARγ and upregulating hepatic expression of carnitine palmitoyltransferase-1α (CPT1α) to decrease lipogenesis and increase fatty acid β-oxidation [259].”

What the sources say

• Not checked yetcites [259] Sheng, 2011, Lipocalin 13 protein protects against hepatic steatosis by both inhibiting lipogenesis and stimulating fatty acid β-oxidation, Journal of Biological Chemistry source

In the paper

“SMOC1 is widely expressed in multiple tissues and generally localized at the basement membrane of cells.”

In the paper

“The discrepancies in findings between groups may have been due to the differences in TSK knockout mouse models that were generated and/or variations in diet composition that were used.”

In the paper

“Plasma levels of SMOC1 decrease in patients with insulin-resistance compared with insulin-sensitive individuals and correlate with hepatic and peripheral insulin sensitivity (Table 1).”

In the paper

“SPARC-related modular calcium-binding protein-1 (SMOC1) is a hepatokine recently identified to improve glucose homeostasis in rodents [266].”

What the sources say

• Not checked yetcites [266] Montgomery, 2020, SMOC1 is a glucose-responsive hepatokine and therapeutic target for glycemic control, Science Translational Medicine source

In the paper

“Beneficial hepatokines that improve metabolic dysfunction include activin-E, ANGPTL4, ANGPTL6, FGF21, GDF15, IGF-1, LCN13, SMOC1, and TSK.”

In the paper

“Their concentrations and effects are altered in response to metabolic stressors, and dysregulation in their signaling can result in pathologies including obesity, type 2 diabetes, and NAFLD.”

In the paper

“The regulation of whole-body energy homeostasis by the liver is a complex process that involves tissue crosstalk through the production of hepatokines and changes in hepatic metabolism in response to metabolic cues and substrates.”

In the paper

“whereas SeP knockout mice showed improved glucose tolerance and insulin resistance [260].”

What the sources say

• Not checked yetcites [260] Misu, 2010, A liver-derived secretory protein, selenoprotein P, causes insulin resistance, Cell Metabolism source

In the paper

“SeP is associated with insulin resistance and increased serum triglyceride, and patients with NAFLD, obesity, and type 2 diabetes have high circulating levels of SeP [260,263,264] (Table 1).”

What the sources say

• Not checked yetcites [260] Misu, 2010, A liver-derived secretory protein, selenoprotein P, causes insulin resistance, Cell Metabolism source
• Not checked yetcites [263] Misu, 2019, Identification of hepatokines involved in pathology of type 2 diabetes and obesity, Endocrine Journal source
• Not checked yetcites [264] Yang, 2011, Serum selenoprotein P levels in patients with type 2 diabetes and prediabetes: implications for insulin resistance, inflammation, and atherosclerosis, Journal of Clinical Endocrinology & Metabolism source

In the paper

“These hepatokines improve whole organism energy homeostasis by accomplishing one or more of the following (1) increasing energy expenditure through brown and beige adipocyte activation, (2) increasing insulin sensitivity, (3) increasing glucose uptake, (4) decreasing plasma triglyceride concentrations and regulating cholesterol homeostasis, (5) decreasing body weight, and (6) lowering food intake.”

In the paper

“Chronic decreased levels of detrimental hepatokines, including ANGPTL3, ANGPTL8, fetuin-A, hepassocin, LECT-2, and SeP aid in maintaining insulin sensitivity, lipid homeostasis, and healthy body weight by decreasing systemic inflammation and insulin resistance.”

In the paper

“Mice lacking TSK exhibit elevated core body temperatures and are unable to adequately suppress energy expenditure during starvation, leading to greater body weight loss.”