Disruption of brain-derived neurotrophic factor production from individual promoters generates distinct body composition phenotypes in mice

Abstract

Brain-derived neurotrophic factor (BDNF) is a key neuropeptide in the central regulation of energy balance. The Bdnf gene contains nine promoters, each producing specific mRNA transcripts that encode a common protein. We sought to assess the phenotypic outcomes of disrupting BDNF production from individual Bdnf promoters. Mice with an intact coding region but selective disruption of BDNF production from Bdnf promoters I, II, IV, or VI (Bdnf-e1−/−, -e2−/−, -e4−/−, and -e6−/−) were created by inserting an enhanced green fluorescent protein-STOP cassette upstream of the targeted promoter splice donor site. Body composition was measured by MRI weekly from age 4 to 22 wk. Energy expenditure was measured by indirect calorimetry at 18 wk. Food intake was measured in Bdnf-e1−/− and Bdnf-e2−/− mice, and pair feeding was conducted. Weight gain, lean mass, fat mass, and percent fat of Bdnf-e1−/− and Bdnf-e2−/− mice (both sexes) were significantly increased compared with wild-type littermates. For Bdnf-e4−/− and Bdnf-e6−/− mice, obesity was not observed with either chow or high-fat diet. Food intake was increased in Bdnf-e1−/− and Bdnf-e2−/− mice, and pair feeding prevented obesity. Mutant and wild-type littermates for each strain (both sexes) had similar total energy expenditure after adjustment for body composition. These findings suggest that the obesity phenotype observed in Bdnf-e1−/− and Bdnf-e2−/− mice is attributable to hyperphagia and not altered energy expenditure. Our findings show that disruption of BDNF from specific promoters leads to distinct body composition effects, with disruption from promoters I or II, but not IV or VI, inducing obesity.

A subpopulation of Bdnf-e1–expressing glutamatergic neurons in the lateral hypothalamus critical for thermogenesis control

“…In a recent study, McAllan et al. reported a hyperphagia phenotype in the same Bdnf -e1 −/− mice [67]. However, under our experimental conditions, we have not seen an obvious hyperphagia phenotype (Figure S10).…”

Intronic enhancer region governs transcript-specific Bdnf expression in rodent neurons

“…Similar expression patterns for different BDNF transcripts are also observed in humans ( Pruunsild et al, 2007 ). Notably, different Bdnf transcripts have distinct contribution to various aspects of neural circuit functions and behavior ( Hallock et al, 2019 ; Hill et al, 2016 ; Maynard et al, 2016 ; Maynard et al, 2018 ; McAllan et al, 2018 ; Sakata et al, 2009 ).…”

Model of Quality Management Applied in Lean Green Agriculture Methodology: A Research in Perú

“…This idea is reinforced by [21], who claim that the sustainability of the application of these good practices guarantees that a model of Lean green philosophy can be maintained over time. In this way, achieving successful results against the environmental impact generated by organizations.…”