which of the following best describes the effect of insulin binding to the receptor on the osteoblast cells?
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Insulin receptor signaling in osteoblasts regulates postnatal bone acquisition and body composition
Global energy balance in mammals is controlled by the actions of circulating hormones that coordinate fuel production and utilization in metabolically active tissues. Bone-derived osteocalcin, in its undercarboxylated, hormonal form, regulates fat deposition ...
Cell. Author manuscript; available in PMC 2011 Jul 23.
Published in final edited form as:
Cell. 2010 Jul 23; 142(2): 309–319.
doi: 10.1016/j.cell.2010.06.002
PMCID: PMC2925155
NIHMSID: NIHMS213522
PMID: 20655471
Insulin receptor signaling in osteoblasts regulates postnatal bone acquisition and body composition
Keertik Fulzele,1,9,* Ryan C. Riddle,1,9 Xuemei Cao,1,2 Chao Wan,1 Dongquan Chen,3 Marie-Claude Faugere,4 Susan Aja,5 Mehboob A. Hussain,6 Jens C. Brüning,7 and Thomas L. Clemens1,8,#
Author information Copyright and License information Disclaimer
The publisher's final edited version of this article is available at Cell
This article has been corrected. See Cell. 2022 February 17; 185(4): 746.See commentary "No bones about it: insulin modulates skeletal remodeling." in Cell, volume 142 on page 198.
See other articles in PMC that cite the published article.
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Abstract
Global energy balance in mammals is controlled by the actions of circulating hormones that coordinate fuel production and utilization in metabolically active tissues. Bone-derived osteocalcin, in its undercarboxylated, hormonal form, regulates fat deposition and is a potent insulin secretagogue. Here, we show that insulin receptor (IR) signaling in osteoblasts controls osteoblast development and osteocalcin expression by suppressing the Runx2 inhibitor Twist2. Mice lacking IR in osteoblasts have low circulating undercarboxylated osteocalcin and reduced bone acquisition due to decreased bone formation and deficient numbers of osteoblasts. With age, these mice develop marked peripheral adiposity and hyperglycemia accompanied by severe glucose intolerance and insulin resistance. The metabolic abnormalities in these mice are improved by infusion of exogenous undercarboxylated osteocalcin. These results indicate the existence of a bone-pancreas endocrine loop through which insulin signaling in the osteoblast ensures osteoblast differentiation and stimulates osteocalcin production, which in turn regulates insulin sensitivity and pancreatic insulin secretion to control glucose homeostasis.
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INTRODUCTION
Management of constant energy supply in an environment of variable food intake is critical for the survival of all terrestrial species. To this end, mammals have evolved intricate networks of local and circulating factors that coordinate energy expenditure by communicating metabolic information between the major organs that produce, store, and utilize energy. The skeleton is a highly metabolic tissue and is increasingly recognized as an important player in the coordination of global energy utilization through its hormonal interactions with other tissues (Fukumoto and Martin, 2009; Lee and Karsenty, 2008). As an example, leptin is a well characterized hormone produced by adipocytes that influences insulin sensitivity (Yamauchi et al., 2001) and also regulates postnatal bone acquisition (Karsenty, 2006). It is now appreciated that leptin acts indirectly on bone by activating sympathetic nerves whose efferent outputs target β2-adrenergic receptors on osteoblasts to regulate their proliferation and differentiation (Ducy et al., 2000; Takeda et al., 2002). Up-regulation of sympathetic tone by leptin has also been shown to inhibit insulin secretion via a mechanism involving the osteoblast (Hinoi et al., 2008).
Several lines of circumstantial evidence suggest that insulin also impacts bone development and physiology by regulating osteoblast function. First, a functional insulin receptor (IR) is expressed by osteoblasts and exposure of primary osteoblasts or osteoblast-like cell lines to physiological levels of insulin increases bone anabolic markers including collagen synthesis (Pun et al., 1989; Rosen and Luben, 1983), alkaline phosphatase production (Kream et al., 1985), and glucose uptake (Ituarte et al., 1989). Second, patients with Type-1 diabetes mellitus (T1DM) can develop early onset osteopenia or osteoporosis (Kemink et al., 2000; Thrailkill, 2000), and have an increased risk of fragility fracture (Janghorbani et al., 2006; Nicodemus and Folsom, 2001), as well as poor bone healing and regeneration following injury (Loder, 1988). Analogous bone abnormalities are observed in animal models of T1DM which also exhibit bone loss (Herrero et al., 1998; Verhaeghe et al., 1990) due to reduced bone formation (Goodman and Hori, 1984; Shires et al., 1981; Verhaeghe et al., 1992; Verhaeghe et al., 1990). Localized insulin delivery accelerates healing in these models by enhancing osteogenesis (Gandhi et al., 2005).
For the hormonal networks described above to function effectively, it is reasonable to suggest that signals emanating from the osteoblast should regulate the action of both insulin and leptin. Osteocalcin, a factor produced only by osteoblasts (Weinreb et al., 1990), is a good candidate to fulfill such a function (Lee et al., 2007). Similar to other hormones, osteocalcin is synthesized as pre-pro-osteocalcin which is processed into pro-osteocalcin in the endoplasmic reticulum. Before being secreted by osteoblasts, osteocalcin undergoes vitamin K-dependent carboxylation on 3 Gla residues which endows the molecule with high affinity for bone matrix. A small portion of osteocalcin remains undercarboxylated and is secreted into the circulation (Delmas et al., 1983). The undercarboxylated form of osteocalcin has been proposed to act as a hormone that links bone to other regulators of glucose homeostasis, including insulin and leptin (Hinoi et al., 2008; Lee et al., 2007).
AP Bio
Study with Quizlet and memorize flashcards terms like Which of the following best describes the hydrolysis of carbohydrates?, Which of the following best describes a characteristic of DNA that makes it useful as hereditary material?, Based on the pedigrees in Figure 1, which of the following best explains the observed pattern of inheritance? and more.
AP Bio - Practice Exam #2 MCQ
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Which of the following best describes the hydrolysis of carbohydrates?
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The addition of a water molecule breaks a covalent bone between sugar monomers
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Which of the following best describes a characteristic of DNA that makes it useful as hereditary material?
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Nucleotide bases in one strand can only be paired with specific bases in the other strand
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Terms in this set (59)
Which of the following best describes the hydrolysis of carbohydrates?
The addition of a water molecule breaks a covalent bone between sugar monomers
Which of the following best describes a characteristic of DNA that makes it useful as hereditary material?
Nucleotide bases in one strand can only be paired with specific bases in the other strand
Based on the pedigrees in Figure 1, which of the following best explains the observed pattern of inheritance?
The trait is an autosomal recessive, because the cross between individuals I-1 and I-2 produced an affected offspring
Which of the following best describes the process by which the bacteria are breaking down the glucose to produce lactic acid?
The bacteria are breaking down sugars in the absence of oxygen
Which of the following was the dependent variable in the researcher's experiment?
pH
Based on the data in Table 1, which of the following is the earliest time point at which there is a statistical difference in average pH between the control and the treatment group?
35 minutes
According to the data, which of the following best explains the results of the experiment?
The pH of the treatment culture was lower than the pH of the control because the chemical increased the bacterial metabolic rate
A mutation in the gene coding for a single-polypeptide enzyme results in the substitution of amino acid serine, which has a polar R group, by the amino acid phenylalanine, which has a non polar R group. When researchers test the catalysis of the normal enzyme and the mutated enzyme, they find that the mutated enzyme has much lower activity than the normal enzyme does.
Which of the following most likely explains how the amino acid substitution has resulted in decreased catalytic activist by the mutated enzyme?
The substitution altered the secondary and tertiary structure of the enzyme so that the mutated enzyme folds into a different shape than the normal enzyme does
Pitcher plants are carnivorous plants that grow in areas where the soil contains low levels of key nutrient such as nitrogen. To obtain these nutrients, most pitcher plants capture prey using traps containing a digestive fluid. The captured prey are then broken down and digested, and the pitcher plant absorbs the nutrients.
The traps of one species of pitcher plant, Nepenthes hemsleyana, do not contain digestive fluid. Instead the provide a suitable place for wooly bats (Kerivoula hardwicki) to sleep. The feces from the bat are released into the trap where nutrients in the feces are absorbed and provide the plant with the nitrogen it needs.
Which of the following best describes the relationship between the pitcher plant and the wooly bat?
The relationship is mutualistic because both the plant and the bat benefit
A particular genetic disorder is associated with a single gene with two alleles. Individuals with two recessive alleles are affected. The prevalence of the disorder is 1 in 6,600.
Assuming the population is in Hardy-Weinberg equilibrium, which of the following is closest to the frequency of carriers in the general population?
0.02430
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Verified questions
BIOLOGY
How is carbon cycled between organisms and the environment?
Verified answer BIOLOGY
Given that all species of life have evolved for the same amount of time since their common origin, how would you respond to someone who characterizes prokaryotes as “primitive”?
Verified answer BIOLOGY
Distinguish between science and pseudoscience.
Verified answer BIOLOGY
Among adults with Turner syndrome, it has been found that a very high proportion are genetic mosaics. These are of two types: In some individuals, the majority of cells are 45, XO, but a minority of cells are 46, XX. In other Turner individuals, the majority of cells are 45, XO, but a minority of cells are 46, XY. Explain how these somatic mosaics could arise.
Insulin Signaling in Osteoblasts Integrates Bone Remodeling and Energy Metabolism: Cell
The broad expression of the insulin receptor suggests that the spectrum of insulin function has not been fully described. A cell type expressing this receptor is the osteoblast, a bone-specific cell favoring glucose metabolism through a hormone, osteocalcin, that becomes active once uncarboxylated. We show here that insulin signaling in osteoblasts is necessary for whole-body glucose homeostasis because it increases osteocalcin activity. To achieve this function insulin signaling in osteoblasts takes advantage of the regulation of osteoclastic bone resorption exerted by osteoblasts.
ARTICLE| VOLUME 142, ISSUE 2, P296-308, JULY 23, 2010
Insulin Signaling in Osteoblasts Integrates Bone Remodeling and Energy Metabolism
Mathieu Ferron 5 Jianwen Wei 5 Tatsuya Yoshizawa 5 Anna Teti Patricia Ducy Gerard Karsenty Show all authors Show footnotes
Open ArchiveDOI:https://doi.org/10.1016/j.cell.2010.06.003
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Summary
The broad expression of the insulin receptor suggests that the spectrum of insulin function has not been fully described. A cell type expressing this receptor is the osteoblast, a bone-specific cell favoring glucose metabolism through a hormone, osteocalcin, that becomes active once uncarboxylated. We show here that insulin signaling in osteoblasts is necessary for whole-body glucose homeostasis because it increases osteocalcin activity. To achieve this function insulin signaling in osteoblasts takes advantage of the regulation of osteoclastic bone resorption exerted by osteoblasts. Indeed, since bone resorption occurs at a pH acidic enough to decarboxylate proteins, osteoclasts determine the carboxylation status and function of osteocalcin. Accordingly, increasing or decreasing insulin signaling in osteoblasts promotes or hampers glucose metabolism in a bone resorption-dependent manner in mice and humans. Hence, in a feed-forward loop, insulin signals in osteoblasts activate a hormone, osteocalcin, that promotes glucose metabolism.
Graphical Abstract
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Highlights
▸ Insulin signaling in mouse osteoblasts increases activity of the hormone osteocalcin ▸ Osteocalcin activation depends on the acidic pH in the bone resorption area ▸ Enhanced osteocalcin activity promotes glucose metabolism via bone resorption ▸ Regulation of glucose metabolism by bone also occurs in humans
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Introduction
Bone is a multitasking tissue with mechanical, hematopoietic, and metabolic functions that result from the tight interplay between two bone-specific cell types, the osteoblast and the osteoclast. Bone also emerged recently as an endocrine organ regulating glucose metabolism (Fukumoto and Martin, 2009), a function that has been ascribed to date only to the osteoblast. The intricacy existing between osteoblasts and osteoclasts raises the prospect, however, that the osteoclast may contribute to the endocrine role of the skeleton.
Bone uses the osteoblast-specific secreted molecule osteocalcin to favor glucose homeostasis. Circulating osteocalcin exists in two forms, carboxylated on 3 glutamate residues or undercarboxylated; the latter form being able to enhance insulin secretion by β-cells, insulin sensitivity and energy expenditure (Lee et al., 2007). Osteocalcin (Ocn), however, is not the only gene expressed in osteoblasts affecting glucose homeostasis. Esp, a gene encoding an intracellular tyrosine phosphatase called OST-PTP exerts, through its osteoblast expression, metabolic functions opposite to those of osteocalcin (Lee et al., 2007). Genetic and biochemical evidence show that Esp acts upstream of Ocn to inhibit its metabolic function. For instance, the metabolic phenotype of Esp−/− mice is fully corrected by removing one allele of Ocn even though Ocn+/− mice have no metabolic phenotype, and the fraction of undercarboxylated osteocalcin is significantly higher in Esp−/− than in wild-type (WT) mouse serum.
The role of the osteoblast in regulating glucose metabolism revealed by these and other findings (Rached et al., 2010a, Yoshizawa et al., 2009) raises questions. The first one is to explain how OST-PTP, an intracellular tyrosine phosphatase, can influence the carboxylation and function of a secreted molecule like osteocalcin. A second issue is to provide evidence that the same bone-dependent regulation of glucose metabolism exists in humans since ESP is a pseudogene in this species (Cousin et al., 2004). A third question of physiological nature looming beyond these observations is whether insulin, in a feedback loop, influences osteocalcin synthesis and/or activity.
The insulin receptor is a tyrosine kinase whose activity must be tightly regulated since it can be activated in the absence of ligand (Kasuga et al., 1983). Receptor tyrosine kinases are often inhibited by protein tyrosine phosphatases (PTPs) (Schlessinger, 2000) and PTP1B, which dephosphorylates the insulin receptor, is a major regulator of insulin signaling in hepatocytes and myocytes (Delibegovic et al., 2007, Delibegovic et al., 2009). The fact that OST-PTP is a tyrosine phosphatase raises the testable hypothesis that the insulin receptor is one of its substrates.
Our understanding of insulin signaling in various tissues has been profoundly altered by the analysis of mutant mouse strains lacking the insulin receptor in only one cell type (Bluher et al., 2002, Bruning et al., 1998, Konner et al., 2007, Kulkarni et al., 1999, Michael et al., 2000). Surprisingly, these studies failed to demonstrate a major influence of insulin signaling in the control of whole-body glucose homeostasis in two classical insulin target tissues, muscle, and white fat (Bluher et al., 2002, Bruning et al., 1998). An implication of these observations is that insulin may act in additional organs in order to maintain glucose homeostasis. This hypothesis is consistent with the fact that the insulin receptor is expressed in many cell types where its functions have not yet been analyzed. This is particularly relevant to the osteoblast since it expresses the insulin receptor and regulates insulin secretion (Figure 1A ) (Lee et al., 2007).
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