Adipose chemokine ligand CX3CL1 contributes to maintaining the hippocampal BDNF level, and the effect is attenuated in advanced age.

Aging alters signaling that involves brain-derived neurotrophic factor (BDNF) in the hippocampus. An adequate level of BDNF is essential for maintaining cognitive function in older adults. Previously, we showed that repeated intraperitoneal administration of the chemokine ligand CX3CL1 modulates peritoneal immune cells and the vagal nerve to increase hippocampal BDNF, consequently improving cognitive decline in aged mice. Here, we examined the contribution of endogenous CX3CL1 in the peritoneal cavity to the age-associated regulation of hippocampal BDNF levels. Hippocampal BDNF protein levels were comparable between 5-month-old and 10-month-old mice but were reduced in 18-month-old. CX3CL1 expression in the visceral adipose tissue, which is prominent in the peritoneal cavity, was also lower in 18-month-old mice than in 10-month-old mice. Visceral adipose tissue-specific knockdown of CX3CL1 reduced hippocampal BDNF levels in 10-month-old mice. Reciprocally, a single intraperitoneal injection of CX3CL1 recovered hippocampal BDNF levels in 18-month-old mice. Moreover, the naturally occurring glucocorticoids, corticosterone and hydrocortisone, increased CX3CL1 expression in a concentration-dependent manner. In the visceral adipose tissue, both protein level and enzymatic activity of the glucocorticoid activating enzyme 11β hydroxysteroid dehydrogenase type 1 (11β-HSD1) were lower in 18-month-old mice than in 10-month-old. Tissue-specific knockdown of 11β-HSD1 in visceral adipose tissue decreased both adipose CX3CL1 expression and hippocampal BDNF levels in 10-month-old mice. Our results demonstrate that adipose CX3CL1 is involved in maintaining hippocampal BDNF levels. This inter-tissue crosstalk is impaired in aged mice due to low 11β-HSD1 expression in visceral adipose tissue, which contributes to the age-associated decline in hippocampal BDNF.