Feeding and fasting controls liver expression of a regulator of G protein signaling (Rgs16) in periportal hepatocytes

Jie Huang,Kan Yu,Victor Pashkov,Thomas M Wilkie,Deborah M Kurrasch,Stephen J Gold

doi:10.1186/1476-5926-5-8

Abstract

BackgroundHeterotrimeric G protein signaling in liver helps maintain carbohydrate and lipid homeostasis. G protein signaling is activated by binding of extracellular ligands to G protein coupled receptors and inhibited inside cells by regulators of G protein signaling (RGS) proteins. RGS proteins are GTPase activating proteins, and thereby regulate Gi and/or Gq class G proteins. RGS gene expression can be induced by the ligands they feedback regulate, and RGS gene expression can be used to mark tissues and cell-types when and where Gi/q signaling occurs. We characterized the expression of mouse RGS genes in liver during fasting and refeeding to identify novel signaling pathways controlling changes in liver metabolism.ResultsRgs16 is the only RGS gene that is diurnally regulated in liver of ad libitum fed mice. Rgs16 transcription, mRNA and protein are up regulated during fasting and rapidly down regulated after refeeding. Rgs16 is expressed in periportal hepatocytes, the oxygen-rich zone of the liver where lipolysis and gluconeogenesis predominates. Restricting feeding to 4 hr of the light phase entrained Rgs16 expression in liver but did not affect circadian regulation of Rgs16 expression in the suprachiasmatic nuclei (SCN).ConclusionRgs16 is one of a subset of genes that is circadian regulated both in SCN and liver. Rgs16 mRNA expression in liver responds rapidly to changes in feeding schedule, coincident with key transcription factors controlling the circadian clock. Rgs16 expression can be used as a marker to identify and investigate novel G-protein mediated metabolic and circadian pathways, in specific zones within the liver.

Highlights

Heterotrimeric G protein signaling in liver helps maintain carbohydrate and lipid homeostasis
Our studies described demonstrate that Rgs16 is a diurnally regulated gene in periportal hepatocytes of the liver, its expression is regulated by feeding and dietary constituents, and Rgs16 can be used as a biomarker to investigate G-protein pathways in liver regulating energy homeostasis
Rgs16 mRNA levels were always up regulated by eight hr into the light phase (Zeitgeber time 8 hr; ZT8) but some variation in expression was observed at ZT12 (Fig 1A, compare ZT12 Day 1 vs Day 2)

Summary

Introduction

Heterotrimeric G protein signaling in liver helps maintain carbohydrate and lipid homeostasis. G protein signaling is activated by binding of extracellular ligands to G protein coupled receptors and inhibited inside cells by regulators of G protein signaling (RGS) proteins. Declining body weight during fasting promotes increased food intake and decreased energy expenditure. Many of the orexigenic and anorexigenic signals providing dynamic control of energy and body weight homeostasis are conveyed by G protein coupled receptors (GPCRs) in the brain and periphery [5,9,10]. We investigate a novel approach to understand how G protein signaling in liver regulates metabolic activity to maintain body weight and energy balance. The activity cycle of heterotrimeric G proteins revolves around receptor-catalyzed guanine nucleotide exchange and GTP hydrolysis on the Gα subunit. RGS proteins of the R4 family, such as Rgs, are feedback inhibitors that can terminate signaling by uncoupling hormone binding from effector protein activation [19,20,21]

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