Female Mice with Selenocysteine tRNA Deletion in Agrp Neurons Maintain Leptin Sensitivity and Resist Weight Gain While on a High-Fat Diet.

Daniel J Torres,Dolph L Hatfield,Katlyn J An,Katherine W Hui,Lucia A Seale,Matthew W Pitts,Ashley N Hanato,Marla J Berry,Bradley A Carlson,Ann C Hashimoto,Stella Maris A Remigio

doi:10.3390/ijms222011010

Abstract

The role of the essential trace element selenium in hypothalamic physiology has begun to come to light over recent years. Selenium is used to synthesize a family of proteins participating in redox reactions called selenoproteins, which contain a selenocysteine residue in place of a cysteine. Past studies have shown that disrupted selenoprotein expression in the hypothalamus can adversely impact energy homeostasis. There is also evidence that selenium supports leptin signaling in the hypothalamus by maintaining proper redox balance. In this study, we generated mice with conditional knockout of the selenocysteine tRNA[Ser]Sec gene (Trsp) in an orexigenic cell population called agouti-related peptide (Agrp)-positive neurons. We found that female TrspAgrpKO mice gain less weight while on a high-fat diet, which occurs due to changes in adipose tissue activity. Female TrspAgrpKO mice also retained hypothalamic sensitivity to leptin administration. Male mice were unaffected, however, highlighting the sexually dimorphic influence of selenium on neurobiology and energy homeostasis. These findings provide novel insight into the role of selenoproteins within a small yet heavily influential population of hypothalamic neurons.

Highlights

As the global obesity pandemic worsens [1], gaining a better understanding of the molecular mechanisms involved is necessary for developing effective treatments
agouti-related peptide (Agrp) neurons of mice results in a phenotype that is protected against and leptin reneurons of mice results in a phenotype that is protected against diet-induced obesity (DIO) and leptin resistance
This protection was only observed in female mice, as male TrspAgrp KO mice mice gained as much and adiposity as controls while on anand and developed gained as much weightweight and adiposity as controls while on an high-fat diet (HFD)

Summary

Introduction

As the global obesity pandemic worsens [1], gaining a better understanding of the molecular mechanisms involved is necessary for developing effective treatments. The role of the essential trace element selenium in supporting hypothalamic function, in response to a high-fat diet (HFD), has begun to come to light [3]. Selenium is used to synthesize selenoproteins, a family of proteins that promote redox balance and support physiological processes such as thyroid hormone metabolism [4] and the inflammatory response [5]. Multiple selenoproteins exhibit high levels of expression that appear to be influenced by changes in nutritional status [6,7]. Mouse models with genetic manipulation of selenoprotein expression targeting the hypothalamus have exhibited significant metabolic repercussions [8,9,10]

Methods

Results

Conclusion