Hepatocyte-derived exosomes from early onset obese mice promote insulin sensitivity through miR-3075

Abstract

In chronic obesity, hepatocytes become insulin resistant and exert important effects on systemic metabolism. Here we show that in early onset obesity (4wks HFD), hepatocytes secrete exosomes which enhance insulin sensitivity both in vitro and in vivo . These beneficial effects were due to exosomal miRNA miR-3075 which is enriched in these hepatocyte exosomes. FA2H is a direct target of miR-3075 and siRNA depletion of FA2H in adipocytes, myocytes, and primary hepatocytes leads to increased insulin sensitivity. In chronic obesity (16–18wks HFD), hepatocyte exosomes promote a state of insulin resistance. These chronic obese hepatocyte exosomes do not directly cause impaired insulin signaling in vitro but do promote proinflammatory activation of macrophages. Taken together, these studies show that in early onset obesity, hepatocytes produce exosomes which express high levels of the insulin sensitizing miR-3075. In chronic obesity, this compensatory effect is lost and hepatocyte-derived exosomes from chronic obese mice promote insulin resistance.

Proteomic analysis reveals exercise training induced remodelling of hepatokine secretion and uncovers syndecan-4 as a regulator of hepatic lipid metabolism

“…This prediction is supported by our finding that exercise-responsive factors secreted from hepatocytes improved skeletal muscle insulin action, reduced liver glucose output and increased liver fatty acid oxidation, adaptations that are often reported with exercise training [ 11 ]. It should be noted that secreted factors other than proteins, including metabolites, lipids and extracellular vesicles (containing lipids, non-coding RNA, proteins) [ 14 , 62 ] are likely to contribute to these metabolic changes. We also identified significant alterations in specific hepatokines with chronic exercise training, including reductions in known mediators of insulin resistance (e.g., dipeptidyl peptidase) [ 34 ] pathological angiogenesis (e.g., pantetheinase) [ 63 ], adipose tissue lipolysis (e.g., cathepsin B) [ 64 ] and fatty acid uptake (e.g., fatty acid binding protein 4).…”

Organokines and Exosomes: Integrators of Adipose Tissue Macrophage Polarization and Recruitment in Obesity

“…Of note, it has been shown that the liver plays an early role in the etiology of metabolic disorders associated with lipid overload and then sends a signal to modulate the metabolic functions of adipose tissue by secreting miRNA-containing hepatocyte-derived EVs ( 99 ). Recently, it has been demonstrated that hepatocyte-derived exosomes from chronic obese mice stimulate the proinflammatory M1-like state of ATMs ( 114 ). Moreover, the proinflammation effects were due to exosomal miR-434-3p, which is enriched in these hepatocyte exosomes and this miRNA can directly promote macrophage polarization towards the M1-like state both in vitro and in vivo ( 114 ).…”

“…Recently, it has been demonstrated that hepatocyte-derived exosomes from chronic obese mice stimulate the proinflammatory M1-like state of ATMs ( 114 ). Moreover, the proinflammation effects were due to exosomal miR-434-3p, which is enriched in these hepatocyte exosomes and this miRNA can directly promote macrophage polarization towards the M1-like state both in vitro and in vivo ( 114 ). Overall, these findings suggest that the liver plays a crucial, active metabolic regulatory role by directing crosstalk with adipose tissue via specific exosomes containing miRNAs.…”

Roles of extracellular vesicles associated non-coding RNAs in Diabetes Mellitus

“…Exosomes enriched in this miRNA and injected in 12-week HFD animals accumulated in the liver, adipose tissue and skeletal muscle and restored insulin sensitivity, as assessed by AKT phosphorylation. Importantly, this increase in insulin signaling in metabolic tissues was translated into whole-body enhanced insulin sensitivity and glucose tolerance in treated mice ( Figure 3 ) ( 96 ).…”