Embryonic ablation of neuronal VGF increases energy expenditure and reduces body weight

Abstract

Germline ablation of VGF, a secreted neuronal, neuroendocrine, and endocrine peptide precursor, results in lean, hypermetabolic, and infertile adult mice that are resistant to diet-, lesion-, and genetically-induced obesity and diabetes (Hahm et al., 1999, 2002). To assess whether this phenotype is predominantly driven by reduced VGF expression in developing and/or adult neurons, or in peripheral endocrine and neuroendocrine tissues, we generated and analyzed conditional VGF knockout mice, obtained by mating loxP-flanked (floxed) Vgf mice with either pan-neuronal Synapsin-Cre- or forebrain alpha-CaMKII-Cre-recombinase-expressing transgenic mice. Adult male and female mice, with conditional ablation of the Vgf gene in embryonic neurons had significantly reduced body weight, increased energy expenditure, and were resistant to diet-induced obesity. Conditional forebrain postnatal ablation of VGF in male mice, primarily in adult excitatory neurons, had no measurable effect on body weight nor on energy expenditure, but led to a modest increase in adiposity, partially overlapping the effect of AAV-Cre-mediated targeted ablation of VGF in the adult ventromedial hypothalamus and arcuate nucleus of floxed Vgf mice (Foglesong et al., 2016), and also consistent with results of icv delivery of the VGF-derived peptide TLQP-21 to adult mice, which resulted in increased energy expenditure and reduced adiposity (Bartolomucci et al., 2006). Because the lean, hypermetabolic phenotype of germline VGF knockout mice is to a great extent recapitulated in Syn-Cre+/−,Vgfflpflox/flpflox mice, we conclude that the metabolic profile of germline VGF knockout mice is largely the result of VGF ablation in embryonic CNS neurons, rather than peripheral endocrine and/or neuroendocrine cells, and that in forebrain structures such as hypothalamus, VGF and/or VGF-derived peptides play uniquely different roles in the developing and adult nervous system.

Genome-Wide Association Study of Body Weight Traits in Chinese Fine-Wool Sheep

“…The AADACL3 (arylacetamide deacetylase like 3) gene located on chromosome 12 that correlated with birth weight participates in fat metabolism [33]. The VGF (nerve growth factor inducible) gene on chromosome 24, which correlates with weaning weight, is involved in regulating the food intake and body weight of animals, with the knockout of the VGF gene in mice leading to weight reduction, in vivo fat reduction, and excessive energy consumption [34][35][36][37]. The VGF gene may also regulate fat synthesis and decomposition [38,39].…”

Clearance kinetics of the VGF-derived neuropeptide TLQP-21

“…While the brain is an important target for TLQP-21 based on ligand-receptor binding activity [Possenti et al, 2012], our data now demonstrate that when the peptide is peripherally injected, it does not cross the blood brain barrier. This finding has important implication and suggests that the anti-obesity effect exerted by central [Bartolomucci et al, 2006] and peripheral [Cero et al, 2014] TLQP-21 injection are mediated by different mechanisms [Jiang et al, 2017].…”

Targeted and selective knockout of the TLQP-21 neuropeptide unmasks its unique role in energy homeostasis

“…TLQP-21 is a C-terminal internal fragment, which can only be produced upon cleavage of the precursor TLQP-62 16 . By utilizing gene targeting constructs previously employed to generate the VGF knockout mice 11 and inserting flanking loxP sites into the mouse Vgf locus 26 , we introduced a mutation in the VGF coding sequence (P 573 PAR 576 ccacctgcgcgc to P 573 PAA 576 ccacctgcggcg) leading to R 21 →A mutation ( Figure 2A ). Sanger sequencing confirmed the correct mutation in the ΔTLQP-21 mutated mouse ( Figure 2B ).…”