Leptin receptor reactivation restores brain function in early-life Lepr-deficient mice

Author(s)

Fernandes, Caroline ; Forny-Germano, Leticia ; Andrade, Mayara M. ; Lyra E Silva, Natalia M. ; Ramos-Lobo, Angela M. ; Meireles, Fernanda ; Tovar-Moll, Fernanda ; Houzel, Jean Christophe ; Donato Jr, Jose ; De Felice, Fernanda G.

• Document type: Journal article
• Source: BRAIN; v. 147, n. 8, p. 12-pg., 2024-04-23.

Abstract

Obesity is a chronic disease caused by excessive fat accumulation that impacts the body and brain health. Insufficient leptin or leptin receptor (LepR) is involved in the disease pathogenesis. Leptin is involved with several neurological processes, and it has crucial developmental roles. We have previously demonstrated that leptin deficiency in early life leads to permanent developmental problems in young adult mice, including an imbalance in energy homeostasis, alterations in melanocortin and the reproductive system and a reduction in brain mass. Given that in humans, obesity has been associated with brain atrophy and cognitive impairment, it is important to determine the long-term consequences of early-life leptin deficiency on brain structure and memory function.Here, we demonstrate that leptin-deficient (LepOb) mice exhibit altered brain volume, decreased neurogenesis and memory impairment. Similar effects were observed in animals that do not express the LepR (LepRNull). Interestingly, restoring the expression of LepR in 10-week-old mice reverses brain atrophy, in addition to neurogenesis and memory impairments in older animals.Our findings indicate that leptin deficiency impairs brain development and memory, which are reversible by restoring leptin signalling in adulthood. Fernandes et al. report that mice lacking the leptin receptor show reduced brain volume and neurogenesis as well as memory impairments in association with obesity. Restoring leptin receptor expression reversed the impairments in adult animals, suggesting that leptin-based therapies could help protect the brain from detrimental effects of obesity. (AU)

• FAPESP's process: 20/01318-8 - Central nervous system as a target of growth hormone for the regulation of multiple biological functions
• Grantee: Jose Donato Junior
• Support Opportunities: Research Projects - Thematic Grants