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.
Almost all effective treatments for non-alcoholic fatty liver disease (NAFLD) involve reduction of adiposity, which suggests the metabolic axis between liver and adipose tissue is essential to NAFLD development. Since excessive dietary sugar intake may be an initiating factor for NAFLD, we have characterized the metabolic effects of liquid sucrose intake at concentrations relevant to typical human consumption in mice. We report that sucrose intake induces sexually dimorphic effects in liver, adipose tissue, and the microbiome; differences concordant with steatosis severity. We show that when steatosis is decoupled from impairments in insulin responsiveness, sex is a moderating factor that influences sucrose-driven lipid storage and the contribution of de novo fatty acid synthesis to the overall hepatic triglyceride pool. Our findings provide physiologic insight into how sex influences the regulation of adipose-liver crosstalk and highlight the importance of extrahepatic metabolism in the pathogenesis of diet-induced steatosis and NAFLD.
Alström syndrome is an extremely rare multi-system disorder for which early-onset childhood obesity is one of the cardinal features. Similar to humans with Alström syndrome, animal models with Alms1 loss of function mutations develop obesity, strongly supporting the notion that ALMS1/Alms1 is required for the regulatory control of energy balance across species. To determine which component(s) of energy balance are reliant on functional Alms1, we performed comprehensive energy balance phenotyping of the tvrm102 mouse model of Alström syndrome. We found that that adiposity gains occurred early and rapidly in male mice but much later in females. Rapid increases in body fat in males were, at least in part, due to a marked reduction in energy expenditure during early life and not due to any genotype-specific influence over energy intake. Energy intake did increase in a genotype-specific manner when mice were provided a palatable, high-energy diet, although this was not necessary for the initial establishment of obesity. Interestingly, the energy expenditure deficit observed in male Alms1-/-mice did not persist as mice age, suggesting that loss of Alms1 either causes a developmental delay in the mechanisms controlling early life energy expenditure, or that there is activation of compensatory mechanisms after obesity is established. Future studies will tease out how ALMS1/Alms1 modulates energy expenditure in early life and how sex moderates this process.
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