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

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.

Hypothalamus-skeletal muscle crosstalk during exercise and its role in metabolism modulation.

Physical inactivity is a major public health problem that contributes to the development of several pathologies such as obesity, type 2 diabetes and cardiovascular diseases. Regular exercise mitigates the progression of these metabolic problems and contributes positively to memory and behavior. Therefore, public health agencies have incorporated exercise in the treatment of widespread disorders. The hypothalamus, specifically the ventromedial and the arcuate nuclei, responds to exercise activity and modulates energy metabolism through stimulation of the sympathetic nervous system and catecholamine secretion into the circulation. In addition, physical performance enhances cognitive functions and memory, mediated mostly by an increase in brain-derived neurotrophic factor levels in brain. During exercise training, skeletal muscle myofibers remodel their biochemical, morphological and physiological state. Moreover, skeletal muscle interacts with other organs by the release into the circulation of myokines, molecules that exhibit autocrine, paracrine and endocrine functions. Several studies have focused on the role of skeletal muscle and tissues in response to physical activity. However, how the hypothalamus could influence the skeletal muscle task in the context of exercise is less studied. Here, we review recent data about hypothalamus-skeletal muscle crosstalk in response to physical activity and focus on specific aspects such as the neuroendocrinological effects of exercise and the endocrine functions of skeletal muscle, to provide a perspective for future study directions.