A novel hepatokine, HFREP1, plays a crucial role in the development of insulin resistance and type 2 diabetes

Wu, Hung Tsung; Ou, Horng Yih; Hung, Hao Chang; Su, Yu; Lu, Feng Hwa; Wu, Jin Shang; Yang, Yi Ching; Wu, Chao; Chang, Chih Jen

doi:10.1007/s00125-016-3991-7

Cited by 73 publications

(82 citation statements)

References 26 publications

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“…Moreover, it was reported that hepatokines, which are released from the liver, are directly associated with incident type 2 diabetes [35]. Hepatokines, such as selenoprotein P and hepatocyte-derived fibrinogenrelated protein 1, exacerbate hepatic glucose metabolism and insulin signaling, through increasing of hepatic fat accumulation and activation of inflammatory signaling [36,37]. Thus, NAFLD is more associated with incident type 2 diabetes than MetS.…”

Section: Discussionmentioning

confidence: 99%

Impact of fatty liver disease and metabolic syndrome on incident type 2 diabetes; a population based cohort study

Mitsuhashi

Hashimoto

Hamaguchi³

et al. 2017

Endocr J

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Section: Discussionmentioning

confidence: 99%

Impact of fatty liver disease and metabolic syndrome on incident type 2 diabetes; a population based cohort study

Mitsuhashi

Hashimoto

Hamaguchi³

et al. 2017

Endocr J

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“…A questionnaire was administered by trained nurses in order to obtain data on the demographic characteristics, medical history, and health habits of participants. Since diabetes was reported to be associated with plasma FGL1 concentrations, 19 vector encoding FGL1 increased the fat pad size, whereas FGL1-knockdown by lentiviral vector encoding short-hairpin RNA targeted to FGL1 decreased high-fat dietinduced adiposity. In addition, 3T3-L1 adipocytes were used to clarify the possible mechanism of FGL1-induced adipogenesis.…”

Section: Study Subjectsmentioning

confidence: 99%

“…In addition, FGL1 has a rescue role in hyperglycemic crises . Moreover, we showed that FGL1 has an important role in the development of NAFLD and insulin resistance (IR) . Overexpression of FGL1 in the liver increased hepatic lipid accumulation and IR in mice.…”

Section: Introductionmentioning

confidence: 96%

Targeting fibrinogen‐like protein 1 is a novel therapeutic strategy to combat obesity

Chen

Fan

et al. 2019

FASEB j.

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Fibrinogen‐like‐protein 1 (FGL1) is a novel hepatokine that plays an important role in hepatic steatosis and insulin resistance. Although FGL1 expression can be detected in adipose tissues, the functions of FGL1 in adipose tissues are still unknown. In this study, 356 participants with (body mass index (BMI) ≥25 kg/m2; n = 134) or without obesity (BMI <25 kg/m2; n = 222) were recruited, and we found that the plasma FGL1 concentrations were significantly higher in obese group than those of in the normal weight group, and were positively correlated with age, BMI, waist circumference, fat content, plasma glucose at 2 hours during an oral glucose tolerance test, and the insulin sensitivity index. In univariate analyses, BMI, waist circumference, total fat, visceral fat, and subcutaneous fat areas were positively correlated with FGL1 levels. After adjusting for age and gender, obesity indices, including the BMI and different fat areas, remained significantly associated with FGL1 levels. In order to investigate the causal relationship between FGL1 and obesity, animal and cell models were used. Overexpression of FGL1 in epididymal adipose tissue by lentiviral vector encoding FGL1 increased the fat pad size, whereas FGL1‐knockdown by lentiviral vector encoding short‐hairpin RNA targeted to FGL1 decreased high‐fat diet‐induced adiposity. In addition, 3T3‐L1 adipocytes were used to clarify the possible mechanism of FGL1‐induced adipogenesis. FGL1 induced adipogenesis through an ERK1/2‐C/EBPβ‐dependent pathway in 3T3‐L1 adipocytes. These findings highlight the pathophysiological role of FGL1 in obesity, and FGL1 might be a novel therapeutic target to combat obesity.

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“…The intraperitoneal glucose tolerance test (IPGTT) and the intraperitoneal insulin tolerance test (IPITT) were performed as previously described [30]. After 12 h of fasting, the mice were intraperitoneally injected either with 1.0 g/kg glucose or 1.0 U/kg insulin.…”

Section: Glucose and Insulin Tolerance Testsmentioning

confidence: 99%

Stress Aggravates High-Fat-Diet-Induced Insulin Resistance via a Mechanism That Involves the Amygdala and Is Associated with Changes in Neuroplasticity

Tsai

Chen

et al. 2018

Neuroendocrinology

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Background: The notion that exposure to chronic stress predisposes individuals to developing type 2 diabetes (T2D) has gained much attention in recent decades. Long-term stress induces neuroadaptation in the amygdala and increases corticosterone levels. Corticosterone, the major stress hormone in rodents, induces insulin resistance and obesity in mice. However, little is known about whether the stress-induced amygdalar neuroadaptation could promote the risk of T2D. Methods: We used an 11-week high-fat diet (HFD) feeding paradigm to induce insulin dysfunction in mice, followed by implementation of a 10-day social defeat (SD) stress protocol. Results: Mice receiving SD at the beginning of the HFD feeding aggravated HFD-induced insulin resistance and white adipose tissue expansion. HFD mice had higher levels of plasma corticosterone, which was not affected by the SD. The SD stress upregulated the expression of TrkB and synaptotagmin-4 in the amygdala of HFD mice. Bilateral lesions of the central amygdalae before SD stress inhibited the stress-induced aggravating effect without affecting the HFD-induced elevation of plasma corticosterone. Conclusions: Stress aggravates HFD-induced insulin resistance and neuroadaptation in the amygdala. The HFD-induced insulin resistance is amygdala-dependent. Understanding the role of stress-induced amygdalar adaptation in the development of T2D could inform therapies aimed at reducing chronic stressors to decrease the risk for T2D.

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A novel hepatokine, HFREP1, plays a crucial role in the development of insulin resistance and type 2 diabetes

Abstract: These findings highlight the crucial role of HFREP1 in insulin resistance and diabetes, and provide a potential strategy and biomarker for developing therapeutic approaches to combat these diseases.

Cited by 73 publications

References 26 publications

Impact of fatty liver disease and metabolic syndrome on incident type 2 diabetes; a population based cohort study

Impact of fatty liver disease and metabolic syndrome on incident type 2 diabetes; a population based cohort study

Targeting fibrinogen‐like protein 1 is a novel therapeutic strategy to combat obesity

Stress Aggravates High-Fat-Diet-Induced Insulin Resistance via a Mechanism That Involves the Amygdala and Is Associated with Changes in Neuroplasticity

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