The sympathetic tone mediates leptin's inhibition of insulin secretion by modulating osteocalcin bioactivity

Hinoi, Eiichi; Gao, Nan; Jung, Dae Young; Yadav, Vijay K.; Yoshizawa, Tatsuya; Myers, Martin G.; Chua, Streamson C.; Kim, Jason K.; Kaestner, Klaus H.; Karsenty, Gérard

doi:10.1083/jcb.200809113

Cited by 240 publications

(201 citation statements)

References 26 publications

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“…From a mechanistic point of view, islet perifusion assays showed that osteocalcin acts as an insulin secretagogue [3]. Gene expression analyses of islets or cultured beta cell lines further demonstrated that osteocalcin directly enhances the expression of the insulin genes as well as those encoding cyclindependent kinase 4 (Cdk4), cyclin D1 (Ccnd1) and D2 (Ccnd2) [1][2][3]. These findings explain the positive effect that osteocalcin has on both insulin production and beta cell proliferation.…”

Section: Introductionmentioning

confidence: 60%

“…Conversely, the subcutaneous infusion of recombinant osteocalcin into wild-type mice causes an increase in blood insulin levels, enhances glucose tolerance and improves insulin sensitivity [2]. From a mechanistic point of view, islet perifusion assays showed that osteocalcin acts as an insulin secretagogue [3]. Gene expression analyses of islets or cultured beta cell lines further demonstrated that osteocalcin directly enhances the expression of the insulin genes as well as those encoding cyclindependent kinase 4 (Cdk4), cyclin D1 (Ccnd1) and D2 (Ccnd2) [1][2][3].…”

Section: Introductionmentioning

confidence: 99%

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The role of osteocalcin in the endocrine cross-talk between bone remodelling and energy metabolism

2011

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Bone remodelling, which maintains bone mass constant during adulthood, is an energy-demanding process. This, together with the observation that the adipocyte-derived hormone leptin is a major inhibitor of bone remodelling, led to the hypothesis that bone cells regulate energy metabolism through an endocrine mechanism. Studies to test this hypothesis identified osteocalcin, a hormone secreted by osteoblasts, as a positive regulator of insulin secretion, insulin resistance and energy expenditure. Remarkably, insulin signalling in osteoblasts is a positive regulator of osteocalcin production and activation via its ability to indirectly enhance bone resorption by osteoclasts. In contrast, leptin is a potent inhibitor of osteocalcin function through its effect on the sympathetic tone. Hence, osteocalcin is part of a complex signalling network between bone and the organs more classically associated with the regulation of energy homeostasis, such as the pancreas and adipose tissue. This review summarises the molecular and cellular bases of the present knowledge on osteocalcin biology and discusses the potential relevance of osteocalcin to human metabolism and pathology.

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Section: Introductionmentioning

confidence: 60%

Section: Introductionmentioning

confidence: 99%

The role of osteocalcin in the endocrine cross-talk between bone remodelling and energy metabolism

2011

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“…As with all endocrine loops, such a feedforward mechanism implies the existence of a break, and leptin represents at least one putative break that inhibits insulin secretion by inhibiting osteocalcin activity. (12) …”

Section: Insulin a Peripheral Link Between Bone Remodeling And Energmentioning

confidence: 99%

The osteoblast: An insulin target cell controlling glucose homeostasis

Clemens

Karsenty

2010

Journal of Bone and Mineral Research

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The past five years have witnessed the emergence and discovery of unexpected functions played by the skeleton in whole-organism physiology. Among these newly described tasks is the role of bone in the control of energy metabolism, which is achieved through the secretion of osteocalcin, an osteoblasts-derived hormone regulating insulin secretion, insulin sensitivity, and energy expenditure. These initial findings raised several fundamental questions on the nature of insulin action in bone. Discoveries made independently by our two groups have provided answers recently to some of these questions. Through the analysis of mice lacking insulin receptor (InsR) only in osteoblasts, we found that insulin signaling in these cells favors whole-body glucose homeostasis. Importantly, this function of insulin signaling in osteoblasts was achieved through the negative regulation of osteocalcin carboxylation and bioavailability. Our studies also established that insulin signaling in osteoblasts was a positive regulator not only of postnatal bone acquisition but also of bone resorption. Interestingly, it appears that insulin signaling in osteoblasts induced osteocalcin activation by stimulating osteoclast activity. Indeed, the low pH generated during bone resorption is a sufficient means to decarboxylate osteocalcin. Our findings establish that the osteoblast is an important target used by insulin to control whole-body glucose homeostasis and identify bone resorption as the mechanism regulating osteocalcin activation. ß

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“…The osteoblast-specific protein osteocalcin regulates glucose handling through effects on insulin secretion and sensitivity (33). This action is in turn mediated by the adipokine leptin, which inhibits insulin secretion through direct effects on pancreatic ␤-cells (18) and through inhibition of osteocalcin activity (25). The interplay between bone and metabolism has recently been further elucidated by the discovery that the Forkhead family transcription factor FoxO1, a key regulator of insulin handling in multiple tissues, also acts within the osteoblast to control osteocalcin expression and bioactivity (46).…”

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confidence: 99%

Short-term voluntary exercise in the rat causes bone modeling without initiating a physiological stress response

Rosa¹,

Firth²,

Blair³

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

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research has revealed a neuroendocrine connection between the skeleton and metabolism. Exercise alters both bone modeling and energy balance and may be useful in further developing our understanding of this complex interplay. However, research in this field requires an animal model of exercise that does not cause a physiological stress response in the exercised subjects. In this study, we develop a model of short-term voluntary exercise in the female rat that causes bone modeling without causing stress. Rats were randomly assigned to one of three age-matched groups: control, tower climbing, and squat exercise (rising to an erect bipedal stance). Exercise for 21 days resulted in bone modeling as assessed by peripheral quantitative computed tomography. Fecal corticosterone output was used to assess physiological stress at three time points during the study (preexercise, early exercise, and late in the exercise period). There were no differences in fecal corticosterone levels between groups or time points. This model of voluntary exercise in the rat will be useful for future studies of the influence of exercise on the relationship between skeletal and metabolic health and may be appropriate for investigation of the developmental origins of those effects. computed tomography; corticosterone; exercise; metabolism; stress RECENT ADVANCES IN OUR UNDERSTANDING of the dynamic relationship between body structure and metabolism have revealed a neuroendocrine connection between bone remodeling and energy balance, with both bone and fat acting as endocrine organs (14). The osteoblast-specific protein osteocalcin regulates glucose handling through effects on insulin secretion and sensitivity (33). This action is in turn mediated by the adipokine leptin, which inhibits insulin secretion through direct effects on pancreatic ␤-cells (18) and through inhibition of osteocalcin activity (25). The interplay between bone and metabolism has recently been further elucidated by the discovery that the Forkhead family transcription factor FoxO1, a key regulator of insulin handling in multiple tissues, also acts within the osteoblast to control osteocalcin expression and bioactivity (46).Exercise stimulates modeling of the musculoskeletal system (19, 55, 65), alters metabolism (40), and enhances brain function (17), and thus exercise provides an excellent means of exploring the neuroendocrine connection between bone, fat, and energy balance. The rat model of exercise has been used extensively to study the physiological effects of physical activity using such exercise modalities as swimming (24, 32), running (20,29,41,49,52), jumping (57), tower climbing (43), rising to an erect bipedal stance (11, 64), and weight lifting (62). The effects of exercise on bone have been widely characterized in the rat. Ovariectomized rats undergo changes in bone structure that are nearly identical to those seen in human osteoporosis (28,42), and these animals have proven useful for the study of exercise interventions in osteoporosis treatment (36).In examini...

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The sympathetic tone mediates leptin's inhibition of insulin secretion by modulating osteocalcin bioactivity

Cited by 240 publications

References 26 publications

The role of osteocalcin in the endocrine cross-talk between bone remodelling and energy metabolism

The role of osteocalcin in the endocrine cross-talk between bone remodelling and energy metabolism

The osteoblast: An insulin target cell controlling glucose homeostasis

Short-term voluntary exercise in the rat causes bone modeling without initiating a physiological stress response

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