Panico, Giuliana (2025) Effects of exogen ketosis induced by 1,3-butanediol on adipose organ and hippocampus. [Tesi di dottorato]

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Abstract

Ketone bodies (KBs), particularly β-hydroxybutyrate (β-OHB), are increasingly recognized as signaling molecules regulating metabolic and cellular homeostasis beyond their role as alternative energy substrates. However, the tissue-specific physiological effects of KBs remain incompletely understood. To address this issue, a murine model of exogenous ketosis was employed through in vivo administration of 1,3-butanediol (BD), a metabolic precursor of β-OHB, enabling a rapid and controlled elevation of circulating ketone levels and the investigation of both acute and long-term adaptive responses. In rats, BD administration induced sustained increases in plasma β-OHB and, after 14 days of treatment, was associated with reduced energy intake, decreased body weight gain, and alterations in adipocyte diameter compared to control animals. BD-induced ketosis subsequently affected the functionality of white adipose tissue (WAT), brown adipose tissue (BAT), and the hippocampus. In gonadal WAT, BD shifted redox homeostasis toward reductive stress, triggering interconnected endoplasmic reticulum and mitochondrial dysfunctions that culminated in enhanced lipolysis, tissue inflammation, and altered adipokine and cytokine production. In BAT, BD promoted mitochondrial activity and thermogenesis and induced post-translational modifications of mitochondrial proteins through lysine β-hydroxybutyrylation, suggesting a rapid, non-genomic regulation of mitochondrial function. Notably, these effects were detectable within 3 hours of treatment. To discriminate ketone-specific effects from those secondary to reduced energy intake, outcomes were compared with an isoenergetic model of mild caloric restriction, revealing distinct regulatory mechanisms. In parallel, BD-induced ketosis exerted beneficial effects on hippocampal homeostasis, reducing inflammation and oxidative stress, attenuating endoplasmic reticulum stress and autophagy, and increasing levels of BDNF and synaptic proteins. Overall, these findings identify adipose tissues and the hippocampus as key targets of β-OHB signaling and provide new insights into the physiological actions of exogenous ketosis.

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