Estrogen inhibits Dlk1/FA1 production: A potential mechanism for estrogen effects on bone turnover

Abdallah, Basem M.; Bay‐Jensen, Anne‐Christine; Srinivasan, Bhuma; Tabassi, N. Charni-Ben; Garnero, Patrick; Delaissé, Jean Marie; Khosla, Sundeep; Kassem, Moustapha

doi:10.1002/jbmr.444

Cited by 22 publications

(22 citation statements)

References 27 publications

(27 reference statements)

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“…In addition, DLK1 favors bone resorption through a nuclear factor-kB-dependent pathway (13). Consistent with these data, serum levels of DLK1 were increased in estrogen-deficient postmenopausal women (15) and inversely correlated with total bone mineral density (BMD) in patients with anorexia nervosa (16) or hypothalamic amenorrhea (17).…”

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confidence: 38%

DLK1 Regulates Whole-Body Glucose Metabolism: A Negative Feedback Regulation of the Osteocalcin-Insulin Loop

et al. 2015

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The endocrine role of the skeleton in regulating energy metabolism is supported by a feed-forward loop between circulating osteoblast (OB)-derived undercarboxylated osteocalcin (Glu-OCN) and pancreatic b-cell insulin; in turn, insulin favors osteocalcin (OCN) bioactivity. These data suggest the existence of a negative regulation of this cross talk between OCN and insulin. Recently, we identified delta like-1 (DLK1) as an endocrine regulator of bone turnover. Because DLK1 is colocalized with insulin in pancreatic b-cells, we examined the role of DLK1 in insulin signaling in OBs and energy metabolism. We show that Glu-OCN specifically stimulates Dlk1 expression by the pancreas. Conversely, Dlk1-deficient (Dlk1 2/2 ) mice exhibited increased circulating Glu-OCN levels and increased insulin sensitivity, whereas mice overexpressing Dlk1 in OB displayed reduced insulin secretion and sensitivity due to impaired insulin signaling in OB and lowered Glu-OCN serum levels. Furthermore, Dlk1 2/2 mice treated with Glu-OC experienced significantly lower blood glucose levels than Glu-OCN-treated wild-type mice. The data suggest that Glu-OCN-controlled production of DLK1 by pancreatic b-cells acts as a negative feedback mechanism to counteract the stimulatory effects of insulin on OB production of Glu-OCN, a potential mechanism preventing OCN-induced hypoglycemia.A growing body of work indicates that bone is an endocrine organ that regulates glucose metabolism through, in part, the hormone osteocalcin (OCN). OCN signals in b-cells through its bona fide receptor Gprotein-coupled receptor (Gprc6a) to increase b-cell proliferation and insulin secretion and acts on peripheral tissues to increase energy expenditure (1-3). In turn, insulin signaling in osteoblasts (OBs) stimulates the activation of OCN by promoting its decarboxylation (Glu-OCN) through the bone resorption arm of bone remodeling (1,4). The physiological relevance of these findings have been supported through studies demonstrating skeleton as a site of insulin resistance in mice fed a high-fat diet (5). Moreover, patients with a dominant negative mutation in Gprc6a show evidence of glucose intolerance (3). In all likelihood, the Glu-OCN-insulin feed-forward loop must be under a negative regulation to protect from hypoglycemia. Soluble factors responsible for this regulation have not yet been identified despite the demonstrated ability of transcription factors activating transcription factor 4 (ATF4) and forkhead box protein O1 (FoxO1) to regulate glucose metabolism through a negative regulation of OCN bioavailability (6,7). Delta like-1 (DLK1), also known as preadipocyte factor-1 (Pref-1), is a transmembrane protein belonging to the Notch/serrate/delta family (8,9). The full ectodomain of DLK1 is proteolytically cleaved to generate a soluble active protein named fetal antigen-1 (FA1), which is secreted by endocrine cells of pancreas, ovary, Leydig cells of the testis, adrenal glands, and pituitary gland (10). DLK1 has

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confidence: 38%

DLK1 Regulates Whole-Body Glucose Metabolism: A Negative Feedback Regulation of the Osteocalcin-Insulin Loop

et al. 2015

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“…Delta like 1/FA1 has been established as an inhibitor of adipocyte differentiation and fat mass in vitro and in vivo (Abdallah et al, 2004, 2011b). Thus, we studied the inhibitory effect of FA1 on adipogenic differentiation of myotubes as a consequence of FA1-induced down-regulation of the above indicated adipogenic markers.…”

Section: Resultsmentioning

confidence: 99%

FA1 Induces Pro-Inflammatory and Anti-Adipogenic Pathways/Markers in Human Myotubes Established from Lean, Obese, and Type 2 Diabetic Subjects but Not Insulin Resistance

Abdallah¹,

Beck‐Nielsen²,

Gaster³

2013

Front. Endocrinol.

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Aims: Delta like 1/fetal antigen 1 (Dlk1/FA1) is a protein secreted by hormone producing cells in adult human and mice that is known to inhibit adipogenesis. Recent studies demonstrated the role of Dlk1/FA1 in inducing insulin resistance in mice. To investigate the involvement of circulating Dlk1/FA1 in insulin resistance and type 2 diabetes in human subjects, we studied the effects of chronic FA1 on the intermediary metabolism in myotubes established from lean, obese, and type 2 diabetic (T2D) subjects.Methods: Myotube cultures were established from lean and obese control subjects, and obese T2D subjects and treated with soluble FA1 for 4 days supplemented with/without palmitate (PA). Lipid- and glucose metabolism were studied with labeled precursors while quantitative expression of genes was analyzed using real-time PCR.Results: Diabetic myotubes express significantly reduced insulin stimulated glucose metabolism compared to lean myotubes and a significantly decreased basal PA oxidation. Chronic FA1 exposure did not affect the intermediary metabolism in myotubes. Insulin sensitivity of glucose and lipid metabolism was not affected by chronic FA1 exposure in myotubes established from lean, obese, and T2D subjects. Instead, chronic FA1 exposure induced pro-inflammatory cytokines expression (IL-6 and CCL2) in association with reducing adipogenic markers (ADD1, AP2, CD36, and PPARg2) in myotubes. Consistent with this observation, addition of FA1 to cultured myotubes was show to significantly inhibit their differentiation into adipocyte.Conclusion: Our results exclude direct effects of FA1 on glucose and lipid metabolism in cultured myotubes established from lean, obese, and T2D subjects. Therefore, the pathogenesis of FA1-induced IR might mainly be mediated via the FA1-induced stimulation of pro-inflammatory cytokines, which on turn inhibit adipogenesis in human myotubes.

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“…Among the multiple physiopathological mechanisms involved in OA, those related to sex hormone control have been attracting much attention, in particular those involving estrogens [27]. The loss of articular cartilage integrity has been shown in several animal models with estrogen deficiency [28,29,30,31,32] and this pattern was supported by a study by Claassen et al [33], who showed that estradiol could suppress the expression of some degradative proteinases in cultured osteoarthritic chondrocytes. Estrogen deficiency plays a relevant pathogenic role in OA, and estrogen deprivation might exert a double effect on normal cartilage: on the one hand, through the direct action of estrogen itself, and, on the other, through the associated increase in subchondral bone turnover [34].…”

Section: Discussionmentioning

confidence: 99%

Age Dependent Changes in Cartilage Matrix, Subchondral Bone Mass, and Estradiol Levels in Blood Serum, in Naturally Occurring Osteoarthritis in Guinea Pigs

Yan

Tian

Wang

et al. 2014

IJMS

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The Dunkin Hartley (DH) guinea pig is a widely used naturally occurring osteoarthritis model. The aim of this study was to provide detailed evidence of age-related changes in articular cartilage, subchondral bone mineral density, and estradiol levels. We studied the female Dunkin Hartley guinea pigs at 1, 3, 6, 9, and 12 months of age (eight animals in each group). Histological analysis were used to identify degenerative cartilage and electron microscopy was performed to further observe the ultrastructure. Estradiol expression levels in serum were assessed, and matrix metalloproteinase 3 and glycosaminoglycan expression in cartilage was performed by immunohistochemistry. Bone mineral density of the tibia subchondral bone was measured using dual X-ray absorptiometry. Histological analysis showed that the degeneration of articular cartilage grew more severe with increasing age starting at 3 months, coupled with the loss of normal cells and an increase in degenerated cells. Serum estradiol levels increased with age from 1 to 6 months and thereafter remained stable from 6 to 12 months. Matrix metalloproteinase 3 expression in cartilage increased with age, but no significant difference was found in glycosaminoglycan expression between 1- and 3-month old animals. The bone mineral density of the tibia subchondral bone increased with age before reaching a stable value at 9 months of age. Age-related articular cartilage degeneration occurred in Dunkin Hartley guinea pigs beginning at 3 months of age, while no directly positive or negative correlation between osteoarthritis progression and estradiol serum level or subchondral bone mineral density was discovered.

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Estrogen inhibits Dlk1/FA1 production: A potential mechanism for estrogen effects on bone turnover

Cited by 22 publications

References 27 publications

DLK1 Regulates Whole-Body Glucose Metabolism: A Negative Feedback Regulation of the Osteocalcin-Insulin Loop

DLK1 Regulates Whole-Body Glucose Metabolism: A Negative Feedback Regulation of the Osteocalcin-Insulin Loop

FA1 Induces Pro-Inflammatory and Anti-Adipogenic Pathways/Markers in Human Myotubes Established from Lean, Obese, and Type 2 Diabetic Subjects but Not Insulin Resistance

Age Dependent Changes in Cartilage Matrix, Subchondral Bone Mass, and Estradiol Levels in Blood Serum, in Naturally Occurring Osteoarthritis in Guinea Pigs

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