Hypothalamic sex-specific metabolic shift by canagliflozin during aging

Area of Science:

• Neuroscience
• Metabolism
• Endocrinology

Background:

• The hypothalamus regulates metabolism and changes with aging.
• Sodium-glucose co-transporter 2 inhibitors (SGLT2i) like Canagliflozin (Cana) improve metabolic homeostasis.
• Cana has shown potential in extending lifespan and improving metabolic control in aged male mice.

Purpose of the Study:

• To investigate the long- and short-term effects of Cana on hypothalamic metabolic control in aging UM-HET3 mice.
• To determine sex-specific responses to Cana treatment in the hypothalamus.
• To identify molecular mechanisms underlying Cana's effects on aging metabolism.

Main Methods:

• Administration of Cana to UM-HET3 mice starting at 7 months of age.
• Assessment of body weight, fat mass, glucose tolerance, and insulin sensitivity.
• Indirect calorimetry to measure energy expenditure.
• Analysis of hypothalamic gene expression via RNA-sequencing.

Main Results:

• Short-term Cana treatment reduced body weight and fat mass in males, improving glucose tolerance and insulin sensitivity by 12 months.
• Cana increased energy expenditure in males at 12 months and metabolic rates in both sexes long-term.
• Long-term treatment increased orexigenic/anorexigenic projections to the PVH, particularly in females.
• Hypothalamic RNA-seq revealed sex-specific upregulation of insulin signaling, glycogenolysis, neuropeptide signaling, and mitochondrial function pathways, with males showing more pronounced effects.

Conclusions:

• Cana exerts sex-specific effects on hypothalamic metabolic control during aging.
• The drug influences neuroprotection and metabolic pathways in a sex-dependent manner.
• These findings highlight potential sex-specific targets for hypothalamic neuroprotection by Cana in aging.