Abstract
The liver plays a major role in whole-body energy homeostasis by releasing secretory factors, termed hepatokines. To identify novel target genes associated with insulin resistance, we performed a comprehensive analysis of gene expression profiles using a DNA chip method in liver biopsy samples from humans with varying degrees of insulin resistance. Inhibin βE (INHBE) was identified as a novel putative hepatokine with hepatic gene expression that positively correlated with insulin resistance and body mass index in humans. Quantitative real time-PCR analysis also showed an increase in INHBE gene expression in independent liver samples from insulin-resistant human subjects. Additionally, Inhbe gene expression increased in the livers of db/db mice, a rodent model of type 2 diabetes. To preliminarily screen the role of Inhbe in vivo in whole-body energy metabolic status, hepatic mRNA was knocked down with siRNA for Inhbe (siINHBE) in db/db mice. Treatment with siINHBE suppressed body weight gain during the two-week experimental period, which was attributable to diminished fat rather than lean mass. Additionally, treatment with siINHBE decreased the respiratory quotient and increased plasma total ketone bodies compared with treatment with non-targeting siRNA, both of which suggest enhanced whole-body fat utilization. Our study suggests that INHBE functions as a possible hepatokine to alter the whole-body metabolic status under obese insulin-resistant conditions.
Highlights
Subjects with high fasting plasma glucose (FPG) (! 125 mg/dL) and high homeostasis model assessment of insulin resistance (HOMA-IR) were assigned to the Diabetes group or Group 3
Candidate genes were selected by fold change between the Control and Pre-Diabetes groups based on the signal intensity of the probes for each gene in the DNA chip analysis
Selecting candidate genes for each stratification based on the signal intensity for each probe addressed the problem that potentially significant genes with larger signal intensities would not be selected because of smaller degrees of variation of fold changes
Summary
Type 2 diabetes (T2D) is characterized by progressive decline in insulin secretion because of pancreatic β-cell dysfunction and by insulin resistance in the liver and peripheral tissues, such. Identification of a insulin resistance-associated hepatokine from gene expression analysis in human liver research. The funder provided support in the form of salaries for authors MS, MA, Y. The authors from the funder designed the study, collected the data and analyzed data for the animal studies. These authors contributed to analyze DNA chip and prepare the manuscript. The specific roles of these authors are shown in the ‘author contributions’ section
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