HSP60 Deficiency Induces Hypothalamic Leptin Resistance, While Overexpression Restores Leptin Sensitivity and Enhances Mitochondrial Function

Background: Leptin resistance is a key contributor to obesity and type 2 diabetes, yet its molecular mechanisms remain incompletely understood. Mitochondrial dysfunction is also implicated in metabolic disorders, and chaperones such as HSP60 and HSP10 are essential for maintaining mitochondrial protein homeostasis. Dysfunctional mitochondria can lead to oxidative stress and impair leptin signaling, contributing to metabolic dysregulation. This study investigates the role of HSP60 deficiency in leptin resistance and explores how HSP60/10 overexpression enhances mitochondrial function and might modulate leptin signaling.

Methods: RNA-Seq analysis was performed on hypothalamic tissue from HSP60+/- mice to identify gene expression changes. An ex-vivo study was conducted on hypothalamic slices from HSP60+/- mice. Mitochondrial function, ATP production, and glucose utilization were assessed in neuronal cell lines, CLU468, with HSP60/10 overexpression or HSP60 knockdown.

Results: HSP60+/- mice exhibited hypothalamic leptin resistance, evidenced by no changes in STAT3 phosphorylation after leptin stimulation (p<0.001). HSP60+/--induced brain leptin resistance could be related to oxidative stress. Indeed, RNA-Seq analysis of hypothalamic tissue from heterozygous mice revealed increased oxidative stress pathway activation (p<0.01). Given that HSP60 deficiency impairs mitochondrial function and contributes to leptin resistance, we next investigated whether HSP60/10 overexpression could counteract these effects and restore mitochondrial function. Overexpression of HSP60/10 significantly increased ETC subunit protein expression without altering mRNA levels (p<0.0001) and enhanced ATP production (p<0.0001). Mitochondrial function was markedly improved (p<0.001), leading to enhanced glucose utilization (p<0.0001). Interestingly, we also observed an increase in key glycolytic enzyme protein levels (p<0.05). Additionally, overexpressed cells elevated mitochondrial ribosome mRNA expression (p<0.001), supporting increases in protein expression without corresponding mRNA changes. Notably, these improvements were accompanied by increased leptin sensitivity, as evidenced by robust STAT3 phosphorylation upon leptin stimulation, indicating functional leptin signaling in OE cells [1] [2] [3].

Conclusion: HSP60 deficiency in heterozygous mice leads to hypothalamic leptin resistance, possibly driven by oxidative stress. However, overexpression of HSP60/10 reverses this phenotype with enhanced mitochondrial function and ATP production, highlighting its potential role in metabolic regulation.

Publication History

Article published online:
28 May 2025

• Literatur

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