Central leptin versus ghrelin: effects on bone marrow adiposity and gene expression

Ambati, Suresh; Li, Qiang; Rayalam, Srujana; Hartzell, Diane L.; Della‐Fera, Mary Anne; Hamrick, Mark W.; Baile, Clifton A.

doi:10.1007/s12020-009-9274-z

Cited by 29 publications

(21 citation statements)

References 28 publications

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“…Hypothalamic leptin administration resulted in rapid (within 4-5 days) decreases in peripheral fat as well as bone marrow fat in ob/ob mice (91,92). In the present study, we observed a dramatic decrease in bone marrow adiposity at 5 weeks post-vector administration but this was associated with the surgery; no significant leptin-specific effect was noted.…”

Section: Resultsmentioning

confidence: 99%

Hypothalamic leptin gene therapy prevents weight gain without long-term detrimental effects on bone in growing and skeletally mature female rats

Iwaniec

Boghossian

Trevisiol

et al. 2011

Journal of Bone and Mineral Research

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Hypothalamic leptin gene therapy normalizes the mosaic skeletal phenotype of leptin-deficient ob/ob mice. However, it is not clear whether increased hypothalamic leptin alters bone metabolism in animals already producing the hormone. The objective of this study was to evaluate the long duration effects of recombinant adeno-associated virus-rat leptin (rAAV-Lep) hypothalamic gene therapy on weight gain and bone metabolism in growing and skeletally mature leptin-replete female Sprague-Dawley rats. Rats were either unoperated or implanted with cannulae in the 3rd ventricle of the hypothalamus and injected with either rAAV-Lep or rAAV-GFP (control vector encoding green fluorescent protein) and maintained on standard rat chow fed ad lib for either 5 or 10 weeks (starting at 3 months of age) or 18 weeks (starting at 9 months of age). Tibiae, femora, or lumbar vertebrae were analyzed by microcomputed tomography and/or histomorphometry. In comparison to age-matched rAAV-GFP rats, rAAV-Lep rats maintained a lower body weight for the duration of studies. At 5 weeks post-vector administration, rAAV-Lep rats had lower cancellous bone volume and bone marrow adiposity but higher osteoblast perimeter compared to non-operated controls. However, these values did not differ between the two groups at 10 weeks post-vector administration. Differences in cancellous bone volume and architecture were not detected between the rAAV-Lep and rAAV-GFP groups at either time point. Also, rAAV-Lep had no negative effects on bone in the 9-month old skeletally mature rats at 18 weeks post-vector administration. We hypothesize that the transient reductions in bone mass and bone marrow adiposity at 5 weeks post-vector administration were due to hypothalamic surgery. We conclude that increased hypothalamic leptin, sufficient to prevent weight gain, has minimal specific effects (rAAV-Lep versus rAAV-GFP) on bone metabolism in normal female rats.

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Section: Resultsmentioning

confidence: 99%

Hypothalamic leptin gene therapy prevents weight gain without long-term detrimental effects on bone in growing and skeletally mature female rats

Iwaniec

Boghossian

Trevisiol

et al. 2011

Journal of Bone and Mineral Research

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“…Here, it would be important to ensure that such leptin supplementation does not increase circulating leptin to supraphysiological concentrations. Indeed, exogenous leptin administration also leads to profound MAT loss in animals that are not leptin deficient (34,82,83). In such states of leptin sufficiency, effects of exogenous leptin typically depend upon administration of high doses that elevate circulating leptin to supraphysiological concentrations (84).…”

Section: Endocrine Factors As Potential Mediators Of Crassociated Matmentioning

confidence: 99%

Expansion of Bone Marrow Adipose Tissue During Caloric Restriction Is Associated With Increased Circulating Glucocorticoids and Not With Hypoleptinemia

et al. 2015

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Bone marrow adipose tissue (MAT) accounts for up to 70% of bone marrow volume in healthy adults and increases further in clinical conditions of altered skeletal or metabolic function. Perhaps most strikingly, and in stark contrast to white adipose tissue, MAT has been found to increase during caloric restriction (CR) in humans and many other species. Hypoleptinemia may drive MAT expansion during CR but this has not been demonstrated conclusively. Indeed, MAT formation and function are poorly understood; hence, the physiological and pathological roles of MAT remain elusive. We recently revealed that MAT contributes to hyperadiponectinemia and systemic adaptations to CR. To further these observations, we have now performed CR studies in rabbits to determine whether CR affects adiponectin production by MAT. Moderate or extensive CR decreased bone mass, white adipose tissue mass, and circulating leptin but, surprisingly, did not cause hyperadiponectinemia or MAT expansion. Although this unexpected finding limited our subsequent MAT characterization, it demonstrates that during CR, bone loss can occur independently of MAT expansion; increased MAT may be required for hyperadiponectinemia; and hypoleptinemia is not sufficient for MAT expansion. We further investigated this relationship in mice. In females, CR increased MAT without decreasing circulating leptin, suggesting that hypoleptinemia is also not necessary for MAT expansion. Finally, circulating glucocorticoids increased during CR in mice but not rabbits, suggesting that glucocorticoids might drive MAT expansion during CR. These observations provide insights into the causes and consequences of CR-associated MAT expansion, knowledge with potential relevance to health and disease.

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“…The duration of ICV ghrelin treatment (21 days) in this study could be considered relatively short to induce profound changes in bone mass. However, it should be noted that establishment of an animal model of chronic ICV treatment is technically challenging and the present study is the longest ICV ghrelin treatment attempted (21 days), with previous studies infusing ghrelin for only 6–12 days [8]–[10], [12]. Future study using Alzet osmotic pump model 2ML4 could extend chronic infusion up to 28 days.…”

Section: Discussionmentioning

confidence: 90%

“…Chronic ICV ghrelin infusion increased food intake and weight gain [8], reversed the effect of leptin on food intake [9], increased the glucose utilization rate of adipose tissue [10], and increased lipogenic enzymatic activity in adipose tissue and liver [11]. A recent study investigated the central effects of ghrelin and leptin on body and bone marrow adiposity, as well as adipose tissue and bone marrow gene expression, and reported central ghrelin had no effect on bone marrow adiposity [12]. However, to date, no study has investigated the effect of chronic ICV ghrelin on bone metabolism.…”

Section: Introductionmentioning

confidence: 99%

Chronic Central Administration of Ghrelin Increases Bone Mass through a Mechanism Independent of Appetite Regulation

Choi

Yang

et al. 2013

PLoS ONE

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Leptin plays a critical role in the central regulation of bone mass. Ghrelin counteracts leptin. In this study, we investigated the effect of chronic intracerebroventricular administration of ghrelin on bone mass in Sprague-Dawley rats (1.5 μg/day for 21 days). Rats were divided into control, ghrelin ad libitum-fed (ghrelin ad lib-fed), and ghrelin pair-fed groups. Ghrelin intracerebroventricular infusion significantly increased body weight in ghrelin ad lib-fed rats but not in ghrelin pair-fed rats, as compared with control rats. Chronic intracerebroventricular ghrelin infusion significantly increased bone mass in the ghrelin pair-fed group compared with control as indicated by increased bone volume percentage, trabecular thickness, trabecular number and volumetric bone mineral density in tibia trabecular bone. There was no significant difference in trabecular bone mass between the control group and the ghrelin ad-lib fed group. Chronic intracerebroventricular ghrelin infusion significantly increased the mineral apposition rate in the ghrelin pair-fed group as compared with control. In conclusion, chronic central administration of ghrelin increases bone mass through a mechanism that is independent of body weight, suggesting that ghrelin may have a bone anabolic effect through the central nervous system.

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Central leptin versus ghrelin: effects on bone marrow adiposity and gene expression

Cited by 29 publications

References 28 publications

Hypothalamic leptin gene therapy prevents weight gain without long-term detrimental effects on bone in growing and skeletally mature female rats

Hypothalamic leptin gene therapy prevents weight gain without long-term detrimental effects on bone in growing and skeletally mature female rats

Expansion of Bone Marrow Adipose Tissue During Caloric Restriction Is Associated With Increased Circulating Glucocorticoids and Not With Hypoleptinemia

Chronic Central Administration of Ghrelin Increases Bone Mass through a Mechanism Independent of Appetite Regulation

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