SF1-specific Deletion of the Energy Sensor AMPKγ2 Induces Obesity

Overview

Journal Mol Metab

Specialty Cell Biology

Date 2025 Jan 2

PMID 39746605

Authors

Oscar Freire-Agulleiro

Anxela Estevez-Salguero

Vitor Ferreira

Cassie Lynn Holleman

Julia Garcia-Curras

Ismael Gonzalez-Garcia

Ruben Nogueiras

Manuel Tena-Sempere

Cristina Garcia-Caceres

Carlos Dieguez

Miguel Lopez

Affiliations

Soon will be listed here.

Abstract

Objective: AMP-activated protein kinase (AMPK) is a heterotrimer complex consisting of a catalytic α subunit (α1, α2) with a serine/threonine kinase domain, and two regulatory subunits, β (β1, β2) and γ (γ1, γ2, γ3), encoded by different genes. In the hypothalamus, AMPK plays a crucial role in regulating energy balance, including feeding, energy expenditure, peripheral glucose and lipid metabolism. However, most research on hypothalamic AMPK has concentrated on the catalytic subunits AMPKα1 and AMPKα2, with little focus on the regulatory subunits.

Methods: To fill this gap of knowledge, we investigated the effects of selectively deleting the regulatory isoform AMPKγ2, which is a primary "energy sensor", in steroidogenic factor 1 (SF1) neurons of the ventromedial hypothalamic nucleus (VMH). Complete metabolic phenotyping and molecular analyses in brown adipose tissue (BAT), white adipose tissue (WAT) and liver were carried out.

Results: Our findings reveal that, in contrast to the obesity-protective effect of the genetic deletion of AMPKα subunits, the loss of AMPKγ2 in SF1 neurons leads to a sex-independent and feeding-independent obesity-prone phenotype due to decreased thermogenesis in brown adipose tissue (BAT) and reduced browning of WAT, resulting in lower energy expenditure. Additionally, SF1-Cre AMPKγ2 mice exhibit hepatic lipid accumulation, but surprisingly maintain normal glucose homeostasis.

Conclusions: Overall, these results highlight the distinct roles of AMPK subunits within the hypothalamus.

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