Metabolic sexual dimorphism in hypothalamic Fezf1 neuron-specific BDNF knockout

Area of Science:

• Neuroscience
• Metabolic Research
• Endocrinology

Background:

• Brain-derived neurotrophic factor (BDNF) is crucial for hypothalamic functions including energy balance and metabolism.
• Fezf1 ventromedial hypothalamic (VMH) neurons are identified as a significant source of BDNF.
• Limited knowledge exists on the adult functions of Fezf1 neurons, despite their developmental roles and association with Kallmann syndrome.

Purpose of the Study:

• To characterize Fezf1 neurons in the VMH and their projections.
• To investigate the role of Fezf1-BDNF in regulating the metabolic phenotype of mice.
• To explore potential sex-specific effects of Fezf1-BDNF on metabolism.

Main Methods:

• Utilized a Cre-Lox system for specific expression of mCherry in VMH Fezf1 neurons to map projections via immunofluorescence.
• Generated mice with a Fezf1-specific knockout of BDNF.
• Assessed metabolic phenotypes, including cold tolerance, body weight, food intake, activity levels, glucose tolerance, and insulin sensitivity.

Main Results:

• Identified Fezf1 neuron projections to the dorsomedial hypothalamus and zona incerta.
• Fezf1-BDNF knockout mice exhibited increased cold tolerance in males.
• Females showed protection against diet-induced obesity, reduced food intake, increased spontaneous activity, improved glucose tolerance, and enhanced insulin sensitivity.

Conclusions:

• VMH Fezf1 neurons' distribution and projections are detailed, advancing understanding of their biology.
• BDNF expression in Fezf1 neurons plays a sexually dimorphic role in metabolic regulation.
• This study provides the first evidence of BDNF potentially having a detrimental role in systemic metabolism within a specific hypothalamic population.