Hypothalamic bHLH transcription factors are novel candidates in the regulation of energy balance.
The basic helix-loop-helix transcription factors, neurological basic-helix-loop-helix-2 (Nhlh-2), neurogenic differentiation-1 (NeuroD-1) and single minded-1 (Sim-1) could have roles in energy balance regulation, although supporting evidence is inconclusive. This study in mice provides further evidence that Nhlh-2 and NeuroD-1 are involved in energy balance regulation. In situ hybridization was used to study the expression of the genes in relation to physiological status and genetic background within hypothalamic nuclei that are involved in energy balance regulation. These studies show reduced expression of Nhlh-2 mRNA in the arcuate (ARC) nucleus and NeuroD-1 mRNA in the paraventricular (PVN) nucleus in obese ob/ob and 24 h food-deprived mice relative to respective controls, suggesting regulation by leptin. Interestingly, Nhlh-2 mRNA expression is reduced in obese db/db mice, whereas NeuroD-1 remains unchanged, suggesting different mechanisms of regulation by leptin of these two genes. To study the role of leptin in the regulation of these genes, leptin was injected intraperitoneally in obese ob/ob mice and mRNA expression evaluated after 1 h or 4 h, or after twice-daily injection for 7 days. None of these regimes restored Nhlh-2 or NeuroD-1 to wild-type mRNA levels. These latter data suggest either that the regulation of the Nhlh-2 and NeuroD-1 genes by leptin is indirect or that the apparent leptin insensitivity of the gene expression reflects a developmental deficit that is a consequence of the phenotype of the obese ob/ob mice. The relationship between Nhlh-2 and candidate energy balance-related genes was studied by dual in situ hybridization. Nhlh-2 mRNA was coexpressed in a subpopulation (30%) of ARC neurons expressing pro-opiomelanocortin (POMC) mRNA, suggesting a potential functional relationship.
Nilaweera
Kanishka N
KN
Molecular Neuroendocrinology Group, Rowett Research Institute, Aberdeen Centre for Energy Regulation and Obesity (ACERO), Greenburn Road, Bucksburn, Aberdeen AB21 9SB, Scotland, UK.
Ellis
Claire
C
Barrett
Perry
P
Mercer
Julian G
JG
Morgan
Peter J
PJ
D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins; D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins / Q000235:genetics*; D004302:Dorsomedial Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism; D004734:Energy Metabolism / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D018257:Helix-Loop-Helix Motifs / Q000187:drug effects / Q000235:genetics; D015801:Helminth Proteins / Q000235:genetics*; D006706:Homeostasis / Q000235:genetics*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D020738:Leptin / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009478:Neuropeptide Y / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology
D051792:Basic Helix-Loop-Helix Proteins; D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; D015801:Helminth Proteins; D020738:Leptin; D009478:Neuropeptide Y; D011333:Pro-Opiomelanocortin; D012333:RNA, Messenger; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C106514:HLH-2 protein, C elegans; C501008:Neurod1 protein, mouse; C101750:Sim1 protein, mouse