Bone as a target and mediator of the effects of diet manipulations

Columbia University Health Sciences, New York NY

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Abstract

Abstract Caloric restriction (CR) and time-restricted feeding (TRF) have gained in popularity among clinicians and the general public alike. CR is beneficial in animal models and humans for weight loss and glucose homeostasis but was shown to cause bone loss, although these studies did not systematically considered differences in sex, ages of participants or long-term outcomes. TRF triggers weight loss, lowers glycemia and improves insulin sensitivity but its impact, if any, on bone remodeling remains unclear. This is because very few animal-based studies have been performed and often in combination with other stressors of bone health, and the few clinical studies reported were short- term or in unreliable settings. How CR and TRF affect bones cells is also poorly understood. There is therefore a need for more systematic analyses to define CR/TRF effects on bone health and identify their molecular bases. Although there is an implicit link between TRF and the circadian rhythm, the role of melatonin signaling in the impact of these diets has not been studied in the context of bone biology. Also not known is whether these diets impact the endocrine functions of the skeleton and/or recruit bone-derived hormones to mediate an effect on bone mass/cells or energy metabolism. Both Osteocalcin (Ocn) and Lipocalin2 (Lcn2) have been described by our collective group as osteoblast-derived hormones that regulate glucose homeostasis and energy metabolism but the diet effects on their biology/function has not been evaluated. The goal of this project is therefore to delineate the biological impact of weight-loss diet manipulations on bone structure/mass, cellular and endocrine functions and identify the molecular effectors of this impact. To achieve this, we will: Systematically delineate the impact and molecular basis of the short- and long-term effects of CR and TRF on bone biology. Mice on regular or western diet will be placed on CR, TRF or fed ad lib and short- and long-term effects on the skeleton will be assessed accounting for sex, age at the start of the diet and age-related ovarian failure in females; Determine whether melatonin production/signaling mediates the impact of CR and/or TRF on the skeleton by comparing melatonin proficient to deficient mice and analyzing global, osteoblast- and osteoclast-specific melatonin receptor-deficient mice; Determine whether CR and/or TRF recruit Ocn and/or Lcn2 to mediate these diets effects on bone, glucose and fat metabolisms. These studies will clarify the biological outcome, and provide multiple mechanistic insights, on the impact of a growing therapeutic approach to obesity on both bone mass and bone endocrine functions. They may also suggest modifications that, if implemented during these diet-based therapies, may preserve bone health and as such promote healthy aging.