Opposite Effects of Chronic Central Leptin Infusion on Activation of Insulin Signaling Pathways in Adipose Tissue and Liver Are Related to Changes in the Inflammatory Environment.

Vicente Barrios,Álvaro Martín-Rivada,Ana Campillo-Calatayud,Santiago Guerra-Cantera,Julie A Chowen,Jesús Argente,Laura M Frago,Sandra Canelles

doi:10.3390/biom11111734

Abstract

Leptin modulates insulin signaling and this involves the Akt pathway, which is influenced by changes in the inflammatory environment and with leptin regulating cytokine synthesis. We evaluated the association between activation of the insulin-signaling pathway and alterations in pro- and anti-inflammatory cytokine levels in inguinal fat and liver of chronic central leptin infused (L), pair-fed (PF), and control rats. Signal transducer and activator of transcription 3 (STAT3) phosphorylation was increased in inguinal fat and reduced in liver of L rats. Phosphorylation of c-Jun N-terminal kinase (JNK) and nuclear factor kappa B (NFkB) was increased in inguinal fat of L rats, together with a pro-inflammatory cytokine profile, while in the liver activation of JNK and NFkB were reduced and an anti-inflammatory pattern was found. Phosphorylation of the insulin receptor, Akt and mechanistic target of rapamycin was decreased in inguinal fat and increased in liver of L rats. There was a direct relationship between pSTAT3 and JNK and a negative correlation of Akt with pSTAT3 and JNK in both tissues. These results indicate that the effects of chronically increased leptin on insulin-related signaling are tissue-specific and suggest that inflammation plays a relevant role in the crosstalk between leptin and insulin signaling.

Highlights

Leptin and insulin are major signal molecules involved in the regulation of body weight and energy homeostasis, acting on the hypothalamus and peripheral tissues
We have previously reported that food intake and body weight gain were reduced in the pair-fed rats (PF) and L groups
We show that the percentage of inguinal fat mass was reduced in L rats and no differences in the percentage of liver weight were found among the experimental groups (Table 1)

Summary

Introduction

Leptin and insulin are major signal molecules involved in the regulation of body weight and energy homeostasis, acting on the hypothalamus and peripheral tissues. Their signaling pathways are linked at different levels, including insulin receptor substrate (IRS). Leptin exerts insulin-related metabolic actions through phosphorylation of Janus kinase 2 (JAK2) that can activate IRS and subsequently. The activation of this pathway triggers Akt and mechanistic target of rapamycin (mTOR), which integrates intracellular signaling and extracellular signals, such as nutrients, acting as a key regulator of cellular metabolism [2]. Leptin normally improves systemic insulin sensitivity and body glucose utilization, but this adipokine has differential

Methods

Results

Discussion

Conclusion