Daily leptin blunts marrow fat but does not impact bone mass in calorie-restricted mice

Abstract

Starvation induces low bone mass and high bone marrow adiposity in humans, but the underlying mechanisms are poorly understood. The adipokine leptin falls in starvation, suggesting hypoleptinemia may be a link between negative energy balance, bone marrow fat accumulation and impaired skeletal acquisition. If so, treating mice with leptin during caloric restriction (CR) should reduce marrow adipose tissue (MAT) and improve bone mass. To test this hypothesis, female C57Bl/6J mice were fed a 30% calorie restricted (CR) or normal (N) diet from 5–10 weeks of age, with daily injections of vehicle (VEH), 1 mg/kg leptin (LEP1), or 2 mg/kg leptin (LEP2) (N=6–8/group). Outcomes included body mass, %body fat and whole body bone mineral density (BMD) via pDXA, cortical and trabecular microarchitecture via μCT, and MAT volume via μCT of osmium tetroxide-stained bones. Overall, CR mice had lower body mass, %body fat, BMD, and cortical bone area fraction, but more connected trabeculae, vs. N mice (p<0.05 for all). Most significantly, while MAT was elevated in CR vs. N overall, leptin treatment blunted MAT formation in CR mice by 50% vs. vehicle (p<0.05 for both leptin doses). CR LEP2 mice weighed less vs. CR VEH mice at 9–10 wks of age (p<0.05), but leptin treatment did not affect %body fat, BMD or bone microarchitecture within either diet. These data demonstrate that once daily leptin bolus during CR inhibits bone marrow adipose expansion without affecting bone mass acquisition, suggesting leptin has distinct effects on starvation-induced bone marrow fat formation and skeletal acquisition.

Role of estrogen receptor signaling in skeletal response to leptin in female ob/ob mice

“…In contrast, increases in leptin levels in the hypothalamus of normal rats reduced food intake and body weight without inducing bone loss (Turner et al 2015). However, a combination of caloric restriction (30%) and sc leptin treatment, while reducing MAT accumulation, did not prevent the detrimental skeletal changes associated with suppression of normal weight gain in rapidly growing mice (Devlin, et al 2016). These findings suggest that methods that improve leptin signaling have the potential to preserve bone mass during rapid weight loss in adults but are unlikely to compensate for inadequate energy availability during growth.…”

Exercise Degrades Bone in Caloric Restriction, Despite Suppression of Marrow Adipose Tissue (MAT)

“…(3,72) Increased glucocorticoids, Pref-1, and MAT-derived adiponectin (28,73,74) as well as low IGF-1 and leptin (28,32,(75)(76)(77) have been associated with MAT in CR; however, causality has not been established for these factors in driving MAT nor in the skeletal deterioration of CR. (3,72) Increased glucocorticoids, Pref-1, and MAT-derived adiponectin (28,73,74) as well as low IGF-1 and leptin (28,32,(75)(76)(77) have been associated with MAT in CR; however, causality has not been established for these factors in driving MAT nor in the skeletal deterioration of CR.…”

Development, regulation, metabolism and function of bone marrow adipose tissues

“…For instance, in the absence of BMAT, ovariectomy still causes bone loss in c-kit deficient mice 28 . Similarly, bone loss is also observed in type 1 diabetic mice in which expansion of BMAT is blocked by a PPARγ inhibitor 65 , or leptin administration 66 , and leptin injection to calorie restricted mice decreases BMAT without influencing loss of trabecular and cortical bone 53 . Lastly, certain inbred strains of mice also indicate that the inverse relationship is not universal in that C3H/HeJ mice have both high proximal tibial rBMAT and bone mass, whereas C57Bl/6J mice exhibit low values for both of these variables 21 .…”

“…Although the mechanistic bases for effects of caloric restriction on BMAT remain unknown, a potential cause is increased circulating glucocorticoids 27 , which have been shown to increase marrow adiposity and decrease bone mass 52 . Peripheral or intracerebral administration of leptin decreases rBMAT volume 31, 32 , and leptin administration blocks the increase in rBMAT with calorie restriction 53 ; however, rabbit and rodent data suggest that reduced endogenous leptin concentrations can be dissociated from the BMAT expansion 27 . The disparate effects of calorie restriction on development and/or metabolism of BMAT and WAT provide compelling evidence that BMAs are developmentally and metabolically distinct from white adipocytes.…”