# Metabolic sexual dimorphism in hypothalamic Fezf1 neuron-specific BDNF knockout

## TL;DR

This study shows that BDNF in a specific type of hypothalamic neuron regulates metabolism differently in male and female mice.

## Contribution

The novel finding is that BDNF in Fezf1 neurons has a sex-specific role in regulating metabolism, with protective effects in females and cold tolerance in males.

## Key findings

- Fezf1 neurons in the hypothalamus are a key source of BDNF and project to metabolic control regions.
- Knocking out BDNF in Fezf1 neurons protects female mice from obesity and improves metabolic health.
- BDNF in Fezf1 neurons shows a sexual dimorphic effect, with increased cold tolerance in males.

## Abstract

Brain-derived neurotrophic factor (BDNF) is highly expressed in the hypothalamus where it exerts regulatory functions over neurogenesis, reproduction, energy balance, and metabolism. Analyzing a hypothalamic single-nucleus transcriptomic, we identified Fezf1 ventromedial hypothalamic (VMH) neurons as an important source of BDNF. During development, Fezf1 neurons are involved in the organization of the olfactory bulb, and mutations on this gene are responsible for Kallmann syndrome; however, in adult life, little is known about the functions of Fezf1 neurons.

In this study, we aimed at providing advance in the characterization of Fezf1 neurons and exploring the role of Fezf1-BDNF in the regulation of the metabolic phenotype of mice. Hypothalamic immunofluorescence was employed to determine the distribution and projections of Fezf1 neurons. Mice with a Fezf1-specific knockout of BDNF were constructed and used in the determination of the metabolic phenotype.

Using a Cre-Lox system to express mCherry specifically in Fezf1 neurons of the VMH, we identified projections to the dorsomedial hypothalamus and the zona incerta, regions involved in metabolic control and motor activity, respectively. The Fezf1-specific knockout of BDNF resulted in increased cold tolerance in males, and protection against diet-induced obesity due to a reduction in food intake and increased spontaneous ambulatory activity in females. This was accompanied by protection against glucose intolerance, and increased insulin sensitivity, in females.

Thus, the present work provides advance in the understanding of the biology of VMH Fezf1 neurons, revealing the details of its distribution and projections, and demonstrating that the expression of BDNF in these neurons is involved, according to a sexual dimorphic pattern, in the regulation of metabolic function. In addition, this is the first evidence that, in a specific hypothalamic cell population, BDNF may have a detrimental rather than positive role in the regulation of systemic metabolism.

The online version contains supplementary material available at 10.1186/s13293-025-00770-z.

Fezf1 neurons are an important source of BDNF in the hypothalamus.Hypothalamic Fezf1 neurons project to dorsomedial hypothalamus and the zona incerta.The knockout of BDNF from Fezf1 neurons results in increased cold tolerance in males.The knockout of BDNF from Fezf1 neurons results in protection against diet-induced obesity due to a reduction in food intake and increased spontaneous ambulatory activity in females.

Fezf1 neurons are an important source of BDNF in the hypothalamus.

Hypothalamic Fezf1 neurons project to dorsomedial hypothalamus and the zona incerta.

The knockout of BDNF from Fezf1 neurons results in increased cold tolerance in males.

The knockout of BDNF from Fezf1 neurons results in protection against diet-induced obesity due to a reduction in food intake and increased spontaneous ambulatory activity in females.

The online version contains supplementary material available at 10.1186/s13293-025-00770-z.

The hypothalamus is a brain region involved in the control of functions such as food intake, body temperature, energy expenditure, and reproduction. In this study we show that an important brain substance, namely brain derived neurotrophic factor (BDNF), is expressed in a hypothalamic subpopulation of neurons, FezF1, where it regulates body metabolism according to a sexual dimorphic pattern. In female mice, the inhibition of BDNF in hypothalamic FezF1 neurons result in protection against diet-induced obesity due to a reduction in food intake and increased spontaneous ambulatory activity, whereas in males it leads to increased cold tolerance. The study provides advance in the understanding of how the brain regulates the sexual differences in body metabolism.

The online version contains supplementary material available at 10.1186/s13293-025-00770-z.