Defining the Transcriptional Targets of Leptin Reveals a Role for Atf3 in Leptin Action

Diabetes. 2018 Jun;67(6):1093-1104. doi: 10.2337/db17-1395. Epub 2018 Mar 13.

Abstract

Leptin acts via its receptor (LepRb) to modulate gene expression in hypothalamic LepRb-expressing neurons, thereby controlling energy balance and glucose homeostasis. Despite the importance of the control of gene expression in hypothalamic LepRb neurons for leptin action, the transcriptional targets of LepRb signaling have remained undefined because LepRb cells contribute a small fraction to the aggregate transcriptome of the brain regions in which they reside. We thus employed translating ribosome affinity purification followed by RNA sequencing to isolate and analyze mRNA from the hypothalamic LepRb neurons of wild-type or leptin-deficient (Lepob/ob) mice treated with vehicle or exogenous leptin. Although the expression of most of the genes encoding the neuropeptides commonly considered to represent the main targets of leptin action were altered only following chronic leptin deprivation, our analysis revealed other transcripts that were coordinately regulated by leptin under multiple treatment conditions. Among these, acute leptin treatment increased expression of the transcription factor Atf3 in LepRb neurons. Furthermore, ablation of Atf3 from LepRb neurons (Atf3LepRbKO mice) decreased leptin efficacy and promoted positive energy balance in mice. Thus, this analysis revealed the gene targets of leptin action, including Atf3, which represents a cellular mediator of leptin action.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 3 / agonists*
  • Activating Transcription Factor 3 / chemistry
  • Activating Transcription Factor 3 / genetics
  • Activating Transcription Factor 3 / metabolism
  • Animals
  • Crosses, Genetic
  • Diabetes Mellitus / drug therapy
  • Diabetes Mellitus / metabolism
  • Diabetes Mellitus / pathology
  • Energy Metabolism / drug effects
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation* / drug effects
  • Hypoglycemic Agents / pharmacology
  • Hypoglycemic Agents / therapeutic use
  • Hypothalamus / cytology
  • Hypothalamus / drug effects
  • Hypothalamus / metabolism*
  • Hypothalamus / pathology
  • Leptin / analogs & derivatives
  • Leptin / metabolism*
  • Leptin / pharmacology
  • Leptin / therapeutic use
  • Lipotropic Agents / pharmacology
  • Lipotropic Agents / therapeutic use
  • Male
  • Mice, Knockout
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Nerve Tissue Proteins / agonists
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Neurons / pathology
  • Obesity / drug therapy
  • Obesity / metabolism
  • Obesity / pathology
  • RNA, Messenger / chemistry
  • RNA, Messenger / metabolism
  • Receptors, Leptin / agonists*
  • Receptors, Leptin / genetics
  • Receptors, Leptin / metabolism
  • Sequence Analysis, RNA
  • Signal Transduction* / drug effects

Substances

  • Activating Transcription Factor 3
  • Atf3 protein, mouse
  • Hypoglycemic Agents
  • Leptin
  • Lipotropic Agents
  • Nerve Tissue Proteins
  • RNA, Messenger
  • Receptors, Leptin
  • leptin receptor, mouse
  • metreleptin