# Sex-Specific Cardiovascular Protection in Developing Metabolic Syndrome: The Role of AMPK

## TL;DR

The study explores how AMPK affects cardiovascular risks in metabolic syndrome differently in males and females, highlighting sex-specific protective roles.

## Contribution

The study reveals that AMPK inhibition disrupts estrogen signaling in females, contributing to cardiovascular risks, which is a novel insight into sex-specific metabolic syndrome.

## Key findings

- AMPK inhibition caused cardiovascular issues in females but not until estrogen signaling was disrupted.
- Males showed cardiovascular problems with high-fat diet alone, independent of AMPK.
- AMPK-estrogen pathways may be a therapeutic target for high-risk females and menopausal women.

## Abstract

Metabolic syndrome (MetS) increases the risk of cardiovascular disease development, with sex differences playing a significant role. AMP-activated protein kinase (AMPK), a key regulator of cellular energy homeostasis, becomes dysregulated in MetS, making it a potential therapeutic target. Therefore, we aimed to investigate the role of AMPK in the development of cardiovascular comorbidities in male and female rats with MetS. MetS was induced in young Wistar–Kyoto (WKY) rats through a high-fat diet (HFD; 10 weeks), and the function of AMPK was studied using Compound C (Cmpd C; 1.5 mg/kg, twice per week, during the last 4 weeks). An HFD induced MetS in males, but, in females, it did not affect body weight, blood pressure, or glycemia until AMPK inhibition occurred. Endothelial dysfunction, oxidative stress, and inflammation developed in both HFD male groups, while, in females, these arose only with AMPK inhibition. In both sexes, α1-AMPK activation decreased with eNOS and Nrf2 protein levels after HFD + Cmpd C treatment. Estradiol levels significantly dropped in HFD and Cmpd C females, whereas testosterone levels remained unchanged. Our results suggest that MetS and related cardiovascular comorbidities in males are driven by oxidative stress, inflammation, and endothelial dysfunction, with minimal additive effect of AMPK. In females, MetS arose only when inhibition of AMPK impaired estrogen signalling, emphasising their protective roles. Targeting AMPK-estrogen pathways may provide a therapeutic strategy, particularly for high-risk cardiovascular females and menopausal women.