# Development and characterization of an Sf-1-Flp mouse model

## TL;DR

Researchers created and tested a new mouse model with Flp recombinase in SF-1 neurons to study the VMH's role in physiology.

## Contribution

A novel Sf-1-Flp mouse model was developed and validated for studying VMH-regulated physiology.

## Key findings

- Sf-1-Flp mice show normal fertility and metabolism with no visible phenotypes.
- Optogenetic stimulation of SF-1 neurons increases skeletal muscle PGC-1α, dependent on Adrb2.
- Combining Sf-1-Flp with Cre/LoxP allows conditional deletion of Adrb2 in skeletal muscle.

## Abstract

The use of genetically engineered tools, including combinations of Cre-LoxP and Flp-FRT systems, enables the interrogation of complex biology. Steroidogenic factor-1 (SF-1) is expressed in the ventromedial hypothalamic nucleus (VMH). Development of genetic tools, such as mice expressing Flp recombinase (Flp) in SF-1 neurons (Sf-1-Flp), will be useful for future studies that unravel the complex physiology regulated by the VMH. Here, we developed and characterized Sf-1-Flp mice and demonstrated their utility. The Flp sequence was inserted into the Sf-1 locus with P2A. This insertion did not affect Sf-1 mRNA expression levels and Sf-1-Flp mice do not have any visible phenotypes. They are fertile and metabolically comparable to wild-type littermate mice. Optogenetic stimulation using adeno-associated virus (AAV) carrying Flp-dependent channelrhodopsin-2 (ChR2) increased blood glucose and skeletal muscle PGC-1α in Sf-1-Flp mice. This was similar to SF-1 neuronal activation using Sf-1-BAC-Cre and AAV carrying Cre-dependent ChR2. Finally, we generated Sf-1-Flp mice that lack β2-adrenergic receptors (Adrb2) only in skeletal muscle with a combination of Cre/LoxP technology (Sf-1-Flp:SKMΔAdrb2). Optogenetic stimulation of SF-1 neurons failed to increase skeletal muscle PGC-1α in Sf-1-Flp:SKMΔAdrb2 mice, suggesting that Adrb2 in skeletal muscle is required for augmented skeletal muscle PGC-1α by SF-1 neuronal activation. Our data demonstrate that Sf-1-Flp mice are useful for interrogating complex physiology.

We generated a novel trasngenic animal, Sf-1-Flp mice. We functionally validated the model and demonstrated its utility for untangling complex physiology.