Molecular bases of the regulation of energy expenditure by bone

PROJECT SUMMARY Aging is associated with progressive increases in circulating glucose levels, which are correlated with higher mortality rates. Targeting imbalances in glucose metabolism could thus extend healthy life expectancy. Brown adipose tissue (BAT) generates heat and consumes glucose and fatty acids from the circulation to meet the high energetic demands of thermogenesis. Activation of glucose uptake in BAT by cold or sympathetic mimetics improves glucose homeostasis, lipid metabolism and insulin sensitivity. Moreover, the presence of detectable BAT activity under baseline (i.e. non-stimulated) conditions is associated with lower circulating glucose and triglycerides and decreased risk of type 2 diabetes and cardiometabolic disease. Since glucose uptake in BAT is reduced in aging, restoring BAT function is a promising target to treat age-related hyperglycemia. Metabolic adaptations to cold and high fat that increase glucose uptake, fat utilization and thermogenesis are mediated by melanocortin receptor 4 (MC4R) signaling in a subset of sympathetic preganglionic neurons in the intermediolateral column of the spinal cord (IML). It is presumed that a small subset of proopiomelanocortin neurons in the arcuate nucleus of the hypothalamus that projects to the IML is the exclusive source of MC4R ligand mediating this response. The central hypothesis of this proposal is that bone-derived lipocalin-2 (LCN2) signals via MC4R in sympathetic preganglionic neurons in the spinal cord to enhance metabolic adaptations to chronic cold and high fat diet (HFD) exposure. Studies in Aim 1 will define the temporal dynamics of the effects of aging on adaptations to cold and HFD and will explore the degree to which these deficits can be rescued by MC4R agonists. These experiments will define key time points and metabolic outcomes for mechanistic studies outlined in subsequent Aims. Studies in Aim 2 will use conditional loss of function models to determine whether bone is the main source of LCN2 responsible for metabolic adaptations to cold and HFD. Studies in Aim 3 will determine whether LCN2’s metabolic effects are driven by MC4R signaling in sympathetic preganglionic neurons. Together, these studies will elucidate a new pathway whereby bone-derived hormones influence systemic metabolism via signaling in the spinal cord. If successful, they would support the potential of a bone to spinal cord to brown adipose tissue circuit as a therapeutic target to improve health in aging.