AAV-Mediated Gene Transfer of the Obesity-Associated Gene Etv5 in Rat Midbrain Does Not Affect Energy Balance or Motivated Behavior

Abstract

Several genome-wide association studies have implicated the transcription factor E-twenty- six version 5 (Etv5) in the regulation of body mass index. Further substantiating the role of Etv5 in feeding behavior are the findings that targeted disruption of Etv5 in mice leads to decreased body weight gain and that expression of Etv5 is decreased in the ventral tegmental area and substantia nigra pars compacta (VTA/SNpc) after food restriction. As Etv5 has been suggested to influence dopaminergic neurotransmission by driving the expression of genes that are responsible for the synthesis and release of dopamine, we investigated if expression levels of Etv5 are dependent on nutritional state and subsequently influence the expression levels of tyrosine hydroxylase. While it was shown that Etv5 expression in the VTA/SNpc increases after central administration of leptin and that Etv5 was able to drive expression of tyrosine hydroxylase in vitro, AAV-mediated gene transfer of Etv5 into the VTA/SNpc of rats did not alter expression of tyrosine hydroxylase in vivo. Moreover, AAV-mediated gene transfer of Etv5 in the VTA/SNpc did not affect measures of energy balance or performances in a progressive ratio schedule. Thus, these data do not support a role for increased expression of Etv5 in the VTA/SNpc in the regulation of feeding behavior.

The Drosophila ETV5 Homologue Ets96B: Molecular Link between Obesity and Bipolar Disorder

“…Ets variant 5 ( ETV5 , also known as ERM), an E-twenty-six (ETS) transcription factor belonging to the polyoma enhancer activator 3 (PEA3)-subfamily ( ETV1 , ETV4 and ETV5 ), was initially linked to BMI in a GWAS study [ 8 ]. Experimental evidence in mice also links Etv5 to the regulation of metabolic homeostasis; Etv5 transcriptional expression is affected by ingestion of a high-fat/high-sugar diet, as well as food restriction [ 9 , 10 ]. Moreover, Etv5 -/- mice exhibit decreased body weight compared to controls [ 9 , 10 ].…”

“…Experimental evidence in mice also links Etv5 to the regulation of metabolic homeostasis; Etv5 transcriptional expression is affected by ingestion of a high-fat/high-sugar diet, as well as food restriction [ 9 , 10 ]. Moreover, Etv5 -/- mice exhibit decreased body weight compared to controls [ 9 , 10 ]. In mouse brain, Etv5 is expressed in the arcuate nucleus (ARC), ventro-medial hypothalamus (VMH), substantia nigra (SN), and the ventral tegmental area (VTA) [ 9 ].…”

“…Moreover, Etv5 -/- mice exhibit decreased body weight compared to controls [ 9 , 10 ]. In mouse brain, Etv5 is expressed in the arcuate nucleus (ARC), ventro-medial hypothalamus (VMH), substantia nigra (SN), and the ventral tegmental area (VTA) [ 9 ]. Expression in the ARC and VTA implies involvement in reward-driven or energy-driven food intake [ 11 ].…”

Expression Profiling after Prolonged Experimental Febrile Seizures in Mice Suggests Structural Remodeling in the Hippocampus

“…Primer sequences are listed in S1 File . The synthesis of 33 P RNA-probes and in situ hybridization were performed as described in previous work [ 34 ]. Briefly, sections were hybridized to the 1 x 10 6 cpm of anti-sense 33 P RNA probe in 150 μL hybridization mixture with 50% deionized formamide, 2x standard saline citrate (SSC), 10% dextrane sulphate, 1x Denhardt’s solution, 5 mM ethylenediaminetetraacetic acid (EDTA), and 10 mM phosphate buffer.…”

Discussing the Putative Role of Obesity-Associated Genes in the Etiopathogenesis of Eating Disorders

“…For instance, Etv5-/-mice have been shown to have reduced body weights compared with wild-type controls [179]. In addition, the nutritional state has been shown in animal models to affect the expression of Etv5 in important areas for feeding behavior [180], although this overexpression did not translate into significant changes of eating habits [181]. In any case, it has been suggested that, being a transcription factor, the possibility that ETV5 influences energy balance by transcriptional regulation of key genes linked to food intake in the hypothalamus seems highly likely [161].…”