Cpt1a silencing in AgRP neurons improves cognitive and physical capacity and promotes healthy aging in male mice.

Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 101130839 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1474-9726 (Electronic) Linking ISSN: 14749718 NLM ISO Abbreviation: Aging Cell Subsets: MEDLINE

Publication: Oxford, UK : Wiley-Blackwell
Original Publication: Oxford, UK : Blackwell Pub., c2002-

Carnitine O-Palmitoyltransferase*/genetics ; Carnitine O-Palmitoyltransferase*/metabolism ; Healthy Aging*; Animals ; Male ; Mice ; Agouti-Related Protein/genetics ; Agouti-Related Protein/metabolism ; Arcuate Nucleus of Hypothalamus/metabolism ; Hypothalamus/metabolism ; Neurons/metabolism

Orexigenic neurons expressing agouti-related protein (AgRP) and neuropeptide Y in the arcuate nucleus (ARC) of the hypothalamus are activated in response to dynamic variations in the metabolic state, including exercise. We previously observed that carnitine palmitoyltransferase 1a (CPT1A), a rate-limiting enzyme of mitochondrial fatty acid oxidation, is a key factor in AgRP neurons, modulating whole-body energy balance and fluid homeostasis. However, the effect of CPT1A in AgRP neurons in aged mice and during exercise has not been explored yet. We have evaluated the physical and cognitive capacity of adult and aged mutant male mice lacking Cpt1a in AgRP neurons (Cpt1a KO). Adult Cpt1a KO male mice exhibited enhanced endurance performance, motor coordination, locomotion, and exploration compared with control mice. No changes were observed in anxiety-related behavior, cognition, and muscle strength. Adult Cpt1a KO mice showed a reduction in gastrocnemius and tibialis anterior muscle mass. The cross-sectional area (CSA) of these muscles were smaller than those of control mice displaying a myofiber remodeling from type II to type I fibers. In aged mice, changes in myofiber remodeling were maintained in Cpt1a KO mice, avoiding loss of physical capacity during aging progression. Additionally, aged Cpt1a KO mice revealed better cognitive skills, reduced inflammation, and oxidative stress in the hypothalamus and hippocampus. In conclusion, CPT1A in AgRP neurons appears to modulate health and protects against aging. Future studies are required to clarify whether CPT1A is a potential antiaging candidate for treating diseases affecting memory and physical activity.
(© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

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Grant CB06/03/0001 Biomedical Research Centre in Pathophysiology of Obesity and Nutrition (CIBEROBN); PID2020-114953RB-C21 Ministerio de Ciencia e Innovación

Keywords: AgRP neurons; CPT1A; aging; cognitive behavior; physical activity

0 (Agouti-Related Protein)
EC 2.3.1.21 (Carnitine O-Palmitoyltransferase)
EC 2.3.1.21 (CPT1B protein, mouse)

Date Created: 20231123 Date Completed: 20240216 Latest Revision: 20240708

20240709

PMC10861206

10.1111/acel.14047

37994388