Modulation of cognition and anxiety-like behavior by bone remodeling

Lori Khrimian, Arnaud Obri, Gerard Karsenty

Osteocalcin is a bone-derived hormone that regulates a growing number of physiological functions. Osteocalcin-/- mice have increased anxiety-like behavior and depression, decreased exploratory behavior, and impaired learning and memory. Given that osteocalcin is produced only by osteoblasts, Khrimian et al. asked whether an impairment in osteoblast differentiation and function, as may occur in various skeletal dysplasias or with aging, could affect cognition or anxiety. Their results suggest that a decrease in osteocalcin is indeed the cause for these cognitive impairments.

Objective: Glucagon-like peptides are co-released from enteroendocrine L cells in the gut and preproglucagon (PPG) neurons in the brainstem. PPG-derived GLP-1/2 are probably key neuroendocrine signals for the control of energy balance and glucose homeostasis. The objective of this study was to determine whether activation of PPG neurons per se modulates glucose homeostasis and insulin sensitivity in vivo.

Methods: We generated glucagon (Gcg) promoter-driven Cre transgenic mice and injected excitatory hM3Dq-mCherry AAV into their brainstem NTS. We characterized the metabolic impact of PPG neuron activation on glucose homeostasis and insulin sensitivity using stable isotopic tracers coupled with hyperinsulinemic euglycemic clamp.

Results: We showed that after ip injection of clozapine N-oxide, Gcg-Cre lean mice transduced with hM3Dq in the brainstem NTS downregulated basal endogenous glucose production and enhanced glucose tolerance following ip glucose tolerance test. Moreover, acute activation of PPG neuronsNTS enhanced whole-body insulin sensitivity as indicated by increased glucose infusion rate as well as augmented insulin-suppression of endogenous glucose production and gluconeogenesis. In contrast, insulin-stimulation of glucose disposal was not altered significantly.

Conclusions: We conclude that acute activation of PPG neurons in the brainstem reduces basal glucose production, enhances intraperitoneal glucose tolerance, and augments hepatic insulin sensitivity, suggesting an important physiological role of PPG neurons-mediated circuitry in promoting glycemic control and insulin sensitivity.