Gene expression atlas of energy balance brain regions.

Maria Caterina De Rosa,Claudia A Doege,George Stratigopoulos,Charles A Leduc,Hannah J Glover,Qi Su,Mark W Sleeman,Judith Y Altarejos,Yufeng Shen,Rudolph L Leibel,Wendy K Chung

doi:10.1172/jci.insight.149137

Abstract

Energy balance is controlled by interconnected brain regions in the hypothalamus, brainstem, cortex, and limbic system. Gene expression signatures of these regions can help elucidate the pathophysiology underlying obesity. RNA sequencing was conducted on P56 C57BL/6NTac male mice and E14.5 C57BL/6NTac embryo punch biopsies in 16 obesity-relevant brain regions. The expression of 190 known obesity-associated genes (monogenic, rare, and low-frequency coding variants; GWAS; syndromic) was analyzed in each anatomical region. Genes associated with these genetic categories of obesity had localized expression patterns across brain regions. Known monogenic obesity causal genes were highly enriched in the arcuate nucleus of the hypothalamus and developing hypothalamus. The obesity-associated genes clustered into distinct “modules” of similar expression profile, and these were distinct from expression modules formed by similar analysis with genes known to be associated with other disease phenotypes (type 1 and type 2 diabetes, autism, breast cancer) in the same energy balance–relevant brain regions.

Highlights

Energy balance is controlled by the intricate interplay of gene expression in the hypothalamus, brainstem, cortex, and limbic system (Figure 1A)
RNA-Seq was performed on 57 samples from brain regions from P56 C57BL/6NTac male mice (Figure 1, A and B, Supplemental Figure 1, and Supplemental Figure 2); 9 samples from 4 brain regions from E14.5 C57BL/6NTac mouse embryos (Figure 1, A and B, and Supplemental Figure 3); and 4 samples from 2 mouse embryonic stem cell lines derived from C57BL/6 mice (Supplemental Figure 1); sample description including replicates is given in Supplemental Table 2 and Supplemental Table 3
Canonical neuropeptides involved in the regulation of body weight (e.g., Pomc, Agrp, Oxt) and those involved in other functions that are known to map to distinct regions (e.g., Cartpt, Hcrt, Trh, Crh) show the expected region-specific expression pattern

Summary

Introduction

Energy balance is controlled by the intricate interplay of gene expression in the hypothalamus, brainstem, cortex, and limbic system (Figure 1A). The hypothalamus and brainstem are part of the homeostatic circuitry involved in sensing and controlling the energy status of the organism by integrating multiple peripheral metabolic inputs — homeostatic signals — such as circulating metabolites, gut-derived hormones, and adiposity-related signals (1, 2). Cortical and limbic brain regions form the executive and reward systems of the forebrain corticolimbic appetitive network. Homeostatic, reward, and executive regions are interconnected by extensive neuronal circuits (5). Disturbances in any of these regions or their interconnecting neurocircuitry can lead to an imbalance of food intake and energy expenditure resulting in obesity. To understand the pathogenetic mechanisms of obesity, detailed knowledge about qualitative and quantitative gene expression patterns of these brain regions is essential

Methods

Results

Conclusion