Differential expression of insulin receptor tyrosine kinase inhibitor (fetuin) gene in a model of diet-induced obesity

doi:10.1016/S0024-3205(98)00250-1

Life Sciences

Volume 63, Issue 2, 5 June 1998, Pages 145-153

https://doi.org/10.1016/S0024-3205(98)00250-1 Get rights and content

Abstract

The Differential Display technique has been used to identify differences in mRNA expression in adipose tissue after the introduction of a high fat diet to two strains of rat (OM and S5B/PI) that differ in their susceptibility to develop obesity on this diet. The insulin receptor tyrosine kinase inhibitor protein (fetuin) was shown to be differentially expressed in OM but not S5B/PI rats. This circulating protein may play a role in the development of peripheral insulin resistance associated with high fat diets.

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Cited by (59)

Comparative proteomics reveals genetic mechanisms of body weight in Hu sheep and Dorper sheep
2022, Journal of Proteomics
Citation Excerpt :
Alpha 2-HS glycoprotein (AHSG) is a natural inhibitor of insulin-stimulated IR-TK [69]. AHSG regulation in the liver is associated with rats' susceptibility to diet-induced obesity [70]. Moreover, a previous study has shown that the polymorphism of AHSG was associated with lipolysis of subcutaneous adipocytes [71].
Body weight (BW) is a critical economic trait for meat production in sheep, and it is a complex trait affected by numerous elements. The aim of this study was to investigate the genetic mechanisms of sheep BW by a label-free proteomics approach. The result showed, a total of 27, 14, 61, and 65 differentially abundant proteins (DAPs) were identified in the Hu_HBW vs. Hu_LBW, DP_HBW vs. DP_LBW, Hu_HBW vs. DP_HBW, and Hu_LBW vs. DP_LBW comparisons, respectively. Five proteins (including ILK, AHCYL2, MLIP, CYB5A, and SMTNL1) related to fat synthesis and muscle development were detected in the Hu sheep group. In the Dorper sheep group, the screened DAPs strictly related to muscle development and fat synthesis were significantly enriched in MAP kinase activity (MAPK12), Arachidonic acid metabolism, and Steroid hormone biosynthesis (PGFS, LOC101107119) pathways. Several DAPs related to immune responses (SERPINA1, FGG, SERPINC1, and LOC101108131), fat deposition (APOH, GC, AHSG, SKP1, ACSL1, ACAT1, and ACADS), and muscle development (LMOD3 and LRRC39) were detected in the Hu vs. Dorper sheep comparison. These analyses indicated that the BW of sheep is regulated via a variety of pathways, and these DAPs can be further investigated as candidate markers for predicting the BW of sheep.
Body weight is one of the key traits in sheep and involves multiple coordinated regulatory mechanisms, but the genetic mechanism of BW is still unclear in sheep. In the current study, the label-free method was used to identify the proteins and pathways related to BW using LT muscle of Hu sheep and Dorper sheep with different BW. These findings will provide new candidate proteins and vital pathways into the molecular mechanisms involved growth traits in sheep.
Acute hyperenergetic, high-Fat feeding increases circulating FGF21, LECT2, and fetuin - A in healthy men
2020, Journal of Nutrition
Hepatokines such as fibroblast growth factor 21 (FGF21), leukocyte cell–derived chemotaxin 2 (LECT2), fetuin-A, fetuin-B, and selenoprotein P (SeP) are liver-derived proteins that are modulated by chronic energy status and metabolic disease. Emerging data from rodent and cell models indicate that hepatokines may be sensitive to acute nutritional manipulation; however, data in humans are lacking.
The aim was to investigate the influence of hyperenergetic, high-fat feeding on circulating hepatokine concentrations, including the time course of responses.
In a randomized, crossover design, 12 healthy men [mean ± SD: age, 24 ± 4 y; BMI (kg/m²), 24.1 ± 1.5] consumed a 7-d hyperenergetic, high-fat diet [HE-HFD; +50% energy, 65% total energy as fat (32% saturated, 26% monounsaturated, 8% polyunsaturated)] and control diet (36% total energy as fat), separated by 3 wk. Whole-body insulin sensitivity was assessed before and after each diet using oral-glucose-tolerance tests. Fasting plasma concentrations of FGF21 (primary outcome), LECT2, fetuin-A, fetuin-B, SeP, and related metabolites were measured after 1, 3, and 7 d of each diet. Hepatokine responses were analyzed using 2-factor repeated-measures ANOVA and subsequent pairwise comparisons.
Compared with the control, the HE-HFD increased circulating FGF21 at 1 d (105%) and 3 d (121%;P ≥ 0.040), LECT2 at 3 d (17%) and 7 d (32%;P ≥ 0.004), and fetuin-A at 7 d (7%;P = 0.028). Plasma fetuin-B and SeP did not respond to the HE-HFD. Whole-body insulin sensitivity was reduced after the HE-HFD by 31% (P = 0.021).
Acute high-fat overfeeding augments circulating concentrations of FGF21, LECT2, and fetuin-A in healthy men. Notably, the time course of response varies between proteins and is transient for FGF21. These findings provide further insight into the nutritional regulation of hepatokines in humans and their interaction with metabolic homeostasis. This study was registered at clinicaltrials.govas NCT03369145.
Clinical implications of fetuin-A
2019, Advances in Clinical Chemistry
Fetuin-A, also termed alpha2-Heremans-Schmid glycoprotein, is a 46 kDa hepatocyte derived protein (hepatokine) and serves multifaceted functions.
- (i)
  It acts as systemic inhibitor of extraosseous calcification, serves as transport protein for calcium and phosphate in colloidal calciprotein particles and is involved in bone mineralization. Severe derangements of this system occur in chronic renal disease and are associated with mineral bone disorder. Fetuin-A levels have been associated with survival of renal and transplant patients. Low fetuin-A and high calcification propensity each increase mortality.
- (ii)
  An independent second aspect of fetuin-A is its interaction with the insulin receptor. Associations of fetuin-A levels with metabolic syndrome as well as pursuant atherosclerotic vascular effects have been established. This could be explained by differences in patient characteristics, different stages of vascular calcifications, presence of diabetes and kidney dysfunction.
- (iii)
  A further issue is the acute phase response of fetuin-A to various inflammatory stimuli and injuries. Dependent on the mode of stimulation, fetuin-A may work as a positive or negative acute phase protein. It may also serve as a protective agent in severe systemic inflammation. A suggestive role of fetuin-A may evolve in wasting and malnutrition–inflammation–atherosclerosis syndromes of chronic disease. A novel aspect is the putative role of fetuin-A in adipose tissue inflammation.
- (iv)
  With respect to heart disease, aspects of coronary arterial disease, heart failure and valvular stenosis and calcification have been elucidated. Associations of fetuin-A levels have been found with coronary artery disease, ischemic cardiomyopathy and aortic stenosis.
Impairment of energy sensors, SIRT1 and AMPK, in lipid induced inflamed adipocyte is regulated by Fetuin A
2018, Cellular Signalling
Citation Excerpt :
In recent years, FetA has distinctly entered into the premises of metabolic disorders. Several reports indicate its association with positive energy balance, FetA circulating level rises with high fat fed animals [32,33], overfeeding of healthy human being [34] and obese diabetic patients [35]. Increase in stored energy (hyperlipidemic condition) and concomitant rise in FetA level has also been found to be linked to insulin resistance and type 2 diabetes (T2D) [21,36,37].
Although several reports demonstrated that accumulation of excess lipid in adipose tissue produces defects in adipocyte which leads to the disruption of energy homeostasis causing severe metabolic problems, underlying mechanism of this event remains yet unclear. Here we demonstrate that FetuinA (FetA) plays a critical role in the impairment of two metabolic sensors, SIRT1 and AMPK, in inflamed adipocytes of high fat diet (HFD) mice. A linear increase in adipocyte hypertrophy from 10 to 16 week was in tandem with the increase in FetA and that coincided with SIRT1 cleavage and decrease in pAMPK which adversely affects PGC1α activation. Knock down (KD) of FetA gene in HFD mice could significantly improve this situation indicating FetA's contribution in the damage of energy sensors in inflamed adipocyte. However, FetA effect was not direct, it was mediated through TNF-α which again is dependent on FetA as FetA augments TNF-α expression. FetA being an upstream regulator of TNF-α, its suppression prevented TNF-α mediated Caspase-1 activation and cleavage of SIRT1. FetA induced inactivation of PGC1α due to SIRT1 cleavage decreased PPARϒ, adiponectin, NRF1 and Tfam expression. All these together caused a significant fall in mitochondrial biogenesis and bioenergetics that disrupted energy homeostasis resulting loss of insulin sensitivity. Taken together, our findings revealed a new dimension of FetA, it not only induced inflammation in adipocyte but also acts as an upstream regulator of SIRT1 cleavage and AMPK activation. Intervention of FetA may be worthwhile to prevent metabolic imbalance that causes insulin resistance and type 2 diabetes.
Serum fetuin-A levels in obese and non-obese subjects with and without type 2 diabetes mellitus
2018, Clinica Chimica Acta
Citation Excerpt :
Fetuin-A is an endogenous inhibitor of insulin receptor tyrosine kinase in the liver and muscles [6]. Previous animal experiments indicated that the fetuin-A gene mRNA expression levels were significantly higher in rats fed by high-fat diet than those in low-fat diet [7], but on the contrary, fetuin-A knockout mice showed significantly decreased body fat and resistant to weight gain when fed a high-fat diet compared with wild-type controls [8]. In humans, higher fetuin-A levels have turned out to be an independent risk factor of T2DM [9] and closely associated with insulin resistance and fat accumulation in the liver [10].
Higher fetuin-A expression is linked to both obesity and type 2 diabetes mellitus (T2DM), However, studies in non-obese patients with T2DM are scarce.
345 newly diagnosed T2DM patients and 300 subjects with normal glucose tolerance (NGT) were divided into obese and non-obese subgroups, respectively. Serum fetuin-A and adiponectin levels and related parameters were measured.
T2DM patients with obesity had higher fetuin-A levels compared with non-obese patients and obese NGT subjects (p < 0.001). Significant correlations were observed between fetuin-A and most metabolic parameters in obese NGT and T2DM subjects, but which was not in non-obese patients with T2DM. The independent associations were found between fetuin-A and free fatty acids, HOMA-IR, C-reactive protein and adiponectin only in obese NGT and T2DM subjects (all p < 0.05). The adjusted odds ratios for obesity were increased with increasing quartile of fetuin-A in both T2DM and NGT subjects in logistic regression models (p for trend < 0.001), but which was more significant in T2DM patients.
Higher serum fetuin-A levels in obese T2DM patients compared with non-obese patients and obese NGT subjects supports the hypothesis that fetuin-A may be as a bridge connecting obesity and obesity-related T2DM.
Comparative effects of metformin and pioglitazone on fetuin-A and osteoprotegerin concentrations in patients with newly diagnosed diabetes: A randomized clinical trial
2015, Diabetes and Metabolic Syndrome: Clinical Research and Reviews
Citation Excerpt :
Fetuin-A is predominantly secreted by the liver onto the serum in relatively high concentrations [17]. In fatty livers which favor the development of T2DM, a significant increase in fetuin-A levels [18] and its mRNA [7] expression could be detected, whereas a decrease in liver fat is associated with the decline of plasma fetuin-A [19]. Unlike fetuin-A, OPG is mainly secreted by bone, but is also secreted by a variety of different tissues including endothelial cells and smooth muscle cells.
Fetuin-A is a circulating glycoprotein capable of inhibiting insulin signaling both in vivo and in vitro and is positively associated with insulin resistance. Osteoprotegerin (OPG) acts as a regulatory molecule with increased levels in the early stages of diabetes and atherosclerosis, and is also associated with insulin resistance. We investigated the effects of pioglitazone and metformin as representative insulin-sensitizing therapies on fetuin-A and OPG levels.
In a randomized clinical trial setting (NCT02027103), 88 patients with newly diagnosed type 2 diabetes were randomly assigned to pioglitazone (30 mg/day, n = 46) or metformin (1000 mg/day, n = 42) for 12 weeks. Various anthropometric and metabolic parameters, fetuin-A, OPG, highly sensitive C-reactive protein (hsCRP), and homeostasis model assessment of insulin resistance (HOMA-IR) were measured at baseline and after three months.
The reduction in fasting plasma glucose and haemoglobin A1c levels was comparable in the two arms. Pioglitazone resulted in a significant reduction in both fetuin-A and OPG in men, but only fetuin-A in women. Metformin was only effective in lowering OPG levels in women. When compared, both medications were equally effective with regard to fetuin-A and OPG reduction in women (p = 0.413 and 0.359, respectively). In men, pioglitazone more effectively decreased fetuin-A levels in both uni- (p = 0.011) and multivariate models (p = 0.015) and OPG levels in only uni- (p = 0.023) but not the multivariate model (p = 0.547).
Metformin and pioglitazone differentially affect fetuin-A and osteoprotegrin levels in diabetic women and men. The level of change may not necessarily be associated with the amelioration of insulin resistance.

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Differential expression of insulin receptor tyrosine kinase inhibitor (fetuin) gene in a model of diet-induced obesity

Abstract

Physiol. Behav.

Cell

Physiol. Behav.

Anal. Biochem.

Cell

Prog. Horm. Res.

Biochim. Biophys. Acta

J. Biol. Chem.

Biochem. Biophys. Res. Comm.

Vitam. Horm.

Am. J. Physiol.

Obesity Res.

Obes. Res.

Am. J. Physiol.

Am. J. Physiol.

Cell

Nature

Nature