Skeletal phenotype of the leptin receptor–deficient db/db mouse

Williams, Graham V.; Callon, Karen E.; Watson, Maureen; Costa, Jerome; Ding, Yaoyao; Dickinson, Michelle; Wang, Yudong; Naot, Dorit; Reid, Ian R.; Cornish, Jillian

doi:10.1002/jbmr.367

Cited by 105 publications

(113 citation statements)

References 49 publications

(75 reference statements)

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“…Several reports have shown osteopenia in leptin receptordeficient mice (6,13) with the exception of one (54), which showed high bone mass compared with wt littermates. The current data corroborate the finding of Williams et al (36), showing trabecular osteopenia in ;11-week-old male db mice. In addition, db mice showed severe age-related bone loss.…”

Section: Discussionsupporting

confidence: 93%

Pathophysiological Mechanism of Bone Loss in Type 2 Diabetes Involves Inverse Regulation of Osteoblast Function by PGC-1α and Skeletal Muscle Atrogenes: AdipoR1 as a Potential Target for Reversing Diabetes-Induced Osteopenia

et al. 2015

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Type 2 diabetes is associated with increased fracture risk and delayed facture healing; the underlying mechanism, however, remains poorly understood. We systematically investigated skeletal pathology in leptin receptor–deficient diabetic mice on a C57BLKS background (db). Compared with wild type (wt), db mice displayed reduced peak bone mass and age-related trabecular and cortical bone loss. Poor skeletal outcome in db mice contributed high-glucose– and nonesterified fatty acid–induced osteoblast apoptosis that was associated with peroxisome proliferator–activated receptor γ coactivator 1-α (PGC-1α) downregulation and upregulation of skeletal muscle atrogenes in osteoblasts. Osteoblast depletion of the atrogene muscle ring finger protein-1 (MuRF1) protected against gluco- and lipotoxicity-induced apoptosis. Osteoblast-specific PGC-1α upregulation by 6-C-β-d-glucopyranosyl-(2S,3S)-(+)-5,7,3′,4′-tetrahydroxydihydroflavonol (GTDF), an adiponectin receptor 1 (AdipoR1) agonist, as well as metformin in db mice that lacked AdipoR1 expression in muscle but not bone restored osteopenia to wt levels without improving diabetes. Both GTDF and metformin protected against gluco- and lipotoxicity-induced osteoblast apoptosis, and depletion of PGC-1α abolished this protection. Although AdipoR1 but not AdipoR2 depletion abolished protection by GTDF, metformin action was not blocked by AdipoR depletion. We conclude that PGC-1α upregulation in osteoblasts could reverse type 2 diabetes–associated deterioration in skeletal health.

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Section: Discussionsupporting

confidence: 93%

Pathophysiological Mechanism of Bone Loss in Type 2 Diabetes Involves Inverse Regulation of Osteoblast Function by PGC-1α and Skeletal Muscle Atrogenes: AdipoR1 as a Potential Target for Reversing Diabetes-Induced Osteopenia

et al. 2015

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“…Williams et al (10) compared the bone phenotype of db/db and wild-type mice using microcomputed tomographic analysis. Db/db mice had significantly lower cortical and trabecular bone volume and thickness and a lower trabecular number in the tibias as well as a lower cortical and trabecular bone thickness in the vertebrae (10). These studies suggest an anabolic rather than a catabolic function as well as a central and peripheral mechanism of action of leptin with regard to bone metabolism.…”

Section: Introductionmentioning

confidence: 64%

MECHANISMS IN ENDOCRINOLOGY: The endocrine role of the skeleton: background and clinical evidence

Schwetz

Pieber²,

Obermayer-Pietsch

2012

European Journal of Endocrinology

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Based on the observation that diabetes, obesity, and hypogonadism influence bone metabolism, the existence of a feedback loop and a common regulation was postulated and an endocrine role ascribed to the skeleton. In the first part of this review, two pathways are described whereby adipose tissue acts on bone mass. In the first, leptin activates the sympathetic nervous system via serotonin and diminishes bone mass accrual. The second pathway functions via the activation of CART (CARTPT) and inhibits bone resorption. The first pathway leads to a decrease in bioactivity of the osteoblast-produced hormone osteocalcin (OC) (part 2). In its undercarboxylated form, OC acts on the three targets pancreas, adipose tissue, and gonads (part 3) and thereby causes an increase in insulin secretion and sensitivity, b-cell proliferation, and male fertility. Insulin (part 4) is part of a recently discovered regulatory feedback loop between pancreas and osteoblasts. It is a strong counterplayer of leptin as it causes a decrease in OPG expression and enhances bone resorption and OC decarboxylation. Numerous clinical studies (part 5) have shown associations of total and undercarboxylated OC and markers of energy metabolism. Interventional studies, to date only performed in murine models, have shown positive effects of OC administration on energy metabolism. Whether bone tissue has an even further-reaching endocrine role remains to be elucidated. European Journal of Endocrinology 166 959-967

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“…Leptin signaling can also affect bone morphology [14,15]. Therefore, we measured cortical and total creata were fixed in 4% paraformaldehyde and embedded in paraffin.…”

Section: Insr Overexpression In Db/db Mice Does Not Rescue Bone Defecmentioning

confidence: 99%

Overexpression of insulin receptor partially improves obese and diabetic phenotypes in db/db mice

et al. 2015

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THERE are 347 million diabetic patients worldwide and 95 % of them are type 2 diabetes mellitus (T2DM), hallmarks of which are impaired secretion and action of insulin [1,2]. Several treatment options for T2DM are in clinical use, including injecting insulin, promoting insulin secretion by insulin secretagogues (such as sulfonylureas and glinides), and improving insulin sensitivity by insulin sensitizers (such as biguanides and thiazolidinediones). However, increasing the amount of insulin receptor in insulin-target tissues has not been explored.Insulin exerts its physiological effects through insulin receptors by binding to the alpha subunit of insulin receptor and stimulating the intrinsic kinase activity of the beta subunit [3][4][5]. However, chronic exposure of cells to insulin leads to down-regulation of insulin signaling through a net loss of insulin receptor from the plasma membrane [6], which is one of the mechanisms involved in insulin resistance. Therefore, increasing the amount of insulin receptor could alleviate insulin resistance. Leptin is an adipokine crucial for the regulation of energy homeostasis [7]. A homozygous loss-of-function mutation in the leptin receptor (the db mutation) causes hyperphagia and obesity, leading to diabetes in mice [8,9]. Since obesity is a major risk factor for impaired insulin sensitivity and T2DM, db/db mice are used as a genetic model of T2DM.

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Skeletal phenotype of the leptin receptor–deficient db/db mouse

Cited by 105 publications

References 49 publications

Pathophysiological Mechanism of Bone Loss in Type 2 Diabetes Involves Inverse Regulation of Osteoblast Function by PGC-1α and Skeletal Muscle Atrogenes: AdipoR1 as a Potential Target for Reversing Diabetes-Induced Osteopenia

Pathophysiological Mechanism of Bone Loss in Type 2 Diabetes Involves Inverse Regulation of Osteoblast Function by PGC-1α and Skeletal Muscle Atrogenes: AdipoR1 as a Potential Target for Reversing Diabetes-Induced Osteopenia

MECHANISMS IN ENDOCRINOLOGY: The endocrine role of the skeleton: background and clinical evidence

Overexpression of insulin receptor partially improves obese and diabetic phenotypes in <i>db/db</i> mice

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