Novel roles of miR-199b in regulating fat and bone metabolism

Public Health Problem: The incidence of obesity has reached epidemic proportions worldwide and has contributed to an increase in the risk of numerous chronic disorders-type 2 diabetes-liver pathologies, dyslipidemia, and cardiovascular diseases. Obesity can have negative effects on bone remodeling-reduced mineral density-osteoporosis Imbalance between food intake and energy expenditure-obesity-accumulation of fat mass and energy storage in white adipose tissue (WAT).https://knowledgeconnection.mainehealth.org/lambrew-retreat-2021/1036/thumbnail.jp

IGFBP-2 Directly Stimulates Osteoblast Differentiation: IGFBP-2 DIRECTLY STIMULATES OSTEOBLAST DIFFERENTIATION

Insulin like growth factor binding protein two (IGFBP-2) is important for acquisition of normal bone mass in mice; however, the mechanism by which IGFBP-2 functions is not defined. These studies investigated the role of IGFBP-2 in stimulating osteoblast differentiation. MC-3T3 preosteoblasts expressed IGFBP-2, and IGFBP-2 knockdown resulted in a substantial delay in osteoblast differentiation, reduced osteocalcin expression and Alizarin red staining. These findings were replicated in primary calvarial osteoblasts obtained from IGFBP-2 −/− mice and addition of IGFBP-2 rescued the differentiation program. In contrast, overexpression of IGFBP-2 accelerated the time course of differentiation as well as increasing the total number of differentiating cells. By day 6 IGFBP-2 overexpressing cells expressed twice as much osteocalcin as control cultures and this difference persisted. To determine the mechanism by which IGFBP-2 functions, the interaction between IGFBP-2 and receptor tyrosine phosphatase β (RPTPβ) was examined. Disruption of this interaction inhibited the ability of IGFBP-2 to stimulate AKT activation and osteoblast differentiation. Knockdown of RPTPβ enhanced osteoblast differentiation whereas overexpression of RPTPβ was inhibitory. Adding back IGFBP-2 to RPTPβ overexpressing cells was able to rescue cell differentiation via enhancement of AKT activation. To determine the region of IGFBP-2 that mediated this effect an IGFBP-2 mutant that contained substitutions of key amino acids in the heparin binding domain-1 (HBD-1) was prepared. This mutant had a major reduction in its ability to stimulate differentiation of calvarial osteoblasts from IGFBP-2 −/− mice. Addition of a synthetic peptide that contained the HBD-1 sequence to calvarial osteoblasts from IGFBP-2 −/− mice rescued differentiation and osteocalcin expression. In summary, the results clearly demonstrate that IGFBP-2 stimulates osteoblast differentiation and that this effect is mediated through its heparin binding domain-1 interacting with RPTPβ. The results suggest that stimulation of differentiation is an important mechanism by which IGFBP-2 regulates the acquisition of normal bone mass in mice

Erratum: Insulin-like growth factor-binding protein-2 is required for osteoclast differentiation

Global deletion of the Igfbp2 gene results in the suppression of bone turnover. To investigate the role of IGFBP-2 in regulating osteoclast differentiation we cultured Igfbp2−/− bone marrow cells and found a reduction in the number of osteoclasts and impaired resorption. Addition of full length IGFBP-2 restored osteoclast differentiation, fusion and resorption. To determine the molecular domains of IGFBP-2 that were required for this effect to be manifest, Igfbp2−/− bone marrow cells mice were transfected with constructs in which the heparin binding (HBD) or the IGF- binding domains of IGFBP-2 were mutated. We found that both domains were necessary for osteoclastogenesis since expression of the mutated forms of either domain failed to support the formation of functionally mature osteoclasts. To discern the mechanism by which IGFBP-2 regulates osteoclast formation, PTEN abundance and phosphorylation status as well as AKT responsiveness to IGF-I were analyzed. Igfbp2−/− cells had elevated levels of PTEN and phospho-PTEN compared with controls. Expression of wild-type IGFBP-2 reduced the level of PTEN to that of wild-type cells. Cells expressing the IGF binding mutant showed suppression of PTEN and phospho-PTEN equivalent to the wild type protein, whereas those expressing the IGFBP-2 HBD mutant showed no PTEN suppression. When the ability of IGF-I to stimulate AKT activation, measured by Thr308 and Ser473 phosphorylation, was analyzed, stimulation of Ser473 in response to IGF-I in pre-osteoclasts required the presence of intact IGFBP-2. This effect was duplicated by the addition of a CK2 inhibitor that prevents the phosphorylation of PTEN. In contrast, in fully differentiated osteoclasts stimulation of Thr308 phosphorylation required the presence of intact IGFBP-2. We conclude that IGFBP-2 is an important regulator of osteoclastogenesis and that both the heparin and the IGF binding domains of IGFBP-2 are essential for the formation of fully differentiated and functional osteoclasts

The Lipid Handling Capacity of Subcutaneous Fat Is Programmed by mTORC2 during Development

Overweight and obesity are associated with type 2 diabetes, non-alcoholic fatty liver disease, cardiovascular disease and cancer, but all fat is not equal, as storing excess lipid in subcutaneous white adipose tissue (SWAT) is more metabolically favorable than in visceral fat. Here, we uncover a critical role for mTORC2 in setting SWAT lipid handling capacity. We find that subcutaneous white preadipocytes differentiating without the essential mTORC2 subunit Rictor upregulate mature adipocyte markers but develop a striking lipid storage defect resulting in smaller adipocytes, reduced tissue size, lipid re-distribution to visceral and brown fat, and sex-distinct effects on systemic metabolic fitness. Mechanistically, mTORC2 promotes transcriptional upregulation of select lipid metabolism genes controlled by PPARγ and ChREBP, including genes that control lipid uptake, synthesis, and degradation pathways as well as Akt2, which encodes a major mTORC2 substrate and insulin effector. Further exploring this pathway may uncover new strategies to improve insulin sensitivity.Fil: Hsiao, Wen Yu. University Of Massachussets. Medical School; Estados UnidosFil: Jung, Su Myung. University Of Massachussets. Medical School; Estados UnidosFil: Tang, Yuefeng. University Of Massachussets. Medical School; Estados UnidosFil: Haley, John A.. University Of Massachussets. Medical School; Estados UnidosFil: Li, Rui. University Of Massachussets. Medical School; Estados UnidosFil: Li, Huawei. University Of Massachussets. Medical School; Estados UnidosFil: Martinez Calejman, Camila. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina. University Of Massachussets. Medical School; Estados UnidosFil: Sanchez Gurmaches, Joan. University Of Massachussets. Medical School; Estados Unidos. University of Cincinnati; Estados UnidosFil: Hung, Chien-Min. University Of Massachussets. Medical School; Estados UnidosFil: Luciano, Amelia K.. University Of Massachussets. Medical School; Estados UnidosFil: DeMambro, Victoria. University of Maine; Estados UnidosFil: Wellen, Kathryn E.. University of Pennsylvania; Estados UnidosFil: Rosen, Clifford J.. University of Maine; Estados UnidosFil: Zhu, Lihua Julie. University Of Massachussets. Medical School; Estados UnidosFil: Guertin, David A.. University Of Massachussets. Medical School; Estados Unido

The Lipid Handling Capacity of Subcutaneous Fat Is Programmed by mTORC2 during Development

Overweight and obesity are associated with type 2 diabetes, non-alcoholic fatty liver disease, cardiovascular disease and cancer, but all fat is not equal, as storing excess lipid in subcutaneous white adipose tissue (SWAT) is more metabolically favorable than in visceral fat. Here, we uncover a critical role for mTORC2 in setting SWAT lipid handling capacity. We find that subcutaneous white preadipocytes differentiating without the essential mTORC2 subunit Rictor upregulate mature adipocyte markers but develop a striking lipid storage defect resulting in smaller adipocytes, reduced tissue size, lipid re-distribution to visceral and brown fat, and sex-distinct effects on systemic metabolic fitness. Mechanistically, mTORC2 promotes transcriptional upregulation of select lipid metabolism genes controlled by PPARgamma and ChREBP, including genes that control lipid uptake, synthesis, and degradation pathways as well as Akt2, which encodes a major mTORC2 substrate and insulin effector. Further exploring this pathway may uncover new strategies to improve insulin sensitivity

IGF-1 and Bone: New Discoveries From Mouse Models

Insulin-like growth factor-1 (IGF-1) plays a central role in cellular growth, differentiation, survival, and cell cycle progression. It is expressed early during development and its effects are mediated through binding to a tyrosine kinase receptor, the insulin-like growth factor-1 receptor (IGF-1R). In the circulation, the IGFs bind to IGF-binding proteins (IGFBPs), which determine their bioavailability and regulate the interaction between the IGFs and IGF-1R. Studies in animal models and in humans have established critical roles for IGFs in skeletal growth and development. In this review we present new and old findings from mouse models of the IGF system and discuss their clinical relevance to normal and pathological skeletal physiology. © 2010 American Society for Bone and Mineral Research

First-in-class humanized FSH blocking antibody targets bone and fat

Blocking the action of FSH genetically or pharmacologically in mice reduces body fat, lowers serum cholesterol, and increases bone mass, making an anti-FSH agent a potential therapeutic for three global epidemics: obesity, osteoporosis, and hypercholesterolemia. Here, we report the generation, structure, and function of a first-in-class, fully humanized, epitope-specific FSH blocking antibody with a KD of 7 nM. Protein thermal shift, molecular dynamics, and fine mapping of the FSH-FSH receptor interface confirm stable binding of the Fab domain to two of five receptor-interacting residues of the FSHβ subunit, which is sufficient to block its interaction with the FSH receptor. In doing so, the humanized antibody profoundly inhibited FSH action in cell-based assays, a prelude to further preclinical and clinical testing

Blocking FSH induces thermogenic adipose tissue and reduces body fat

Functional Genomics of Systemic Disorder

EIXO DE INTEGRAÇÃO VIÁRIA: IMPACTOS ECONÔMICOS E SOCIAIS DA BR 158 SOBRE AS CIDADES DO VALE DO ARAGUAIA MATO-GROSSENSE ENTRE 2000 E 2014

Submitted by admin tede ([email protected]) on 2017-05-12T15:03:52Z No. of bitstreams: 1 ELIZEU DEMAMBRO.pdf: 2164594 bytes, checksum: 554f8463ef31b4577e5aa7e6b4f140f4 (MD5)Made available in DSpace on 2017-05-12T15:03:52Z (GMT). No. of bitstreams: 1 ELIZEU DEMAMBRO.pdf: 2164594 bytes, checksum: 554f8463ef31b4577e5aa7e6b4f140f4 (MD5) Previous issue date: 2017-03-07This study seeks to determine the economic and social impacts that highway infrastructure projects caused in cities in the state of Mato Grosso, situated along the BR 158 Highway, such as Barra do Garças, Água Boa, Canarana and Confresa, in the period from 2000 to 2014. Firstly, the role of highway infrastructure investments in promoting the expansion of large monocultures, such as soybeans and corn, was identified. Then, the socioeconomic profile of the region of influence of the BR 158 Highway was characterized, encompassing demography, flow of employment, economic production, exports and imports of the cities, and other items. The study also verified the effects of highway infrastructure investments in the cities in question, in relation to small and medium-sized industrial and commercial segments. Lastly, it identified the goods that are transported and the highway support conditions from the perspective of truck drivers. The methodology used, which was quantitative and qualitative in nature, was supported by instruments, such as observation, interviews, document research and a literature review, with the data presented in the form of comments and tables. In assessing the economic and social impacts of the production changes in the Brazilian cerrado (tropical savanna ecoregion), as a result of highway infrastructure projects, the objective is to help explain the process of regional integration in Mato Grosso, in the current period, and chart it for the upcoming years, based on the infrastructure projects in question.Com este trabalho procurou-se descobrir quais os impactos econômicos e sociais que as obras de infraestrutura viária desencadearam em municípios matogrossenses, situados ao longo da rodovia BR 158, como Barra do Garças, Água Boa, Canarana e Confresa, no período compreendido entre 2000 e 2014. Primeiramente, identificou-se o papel dos investimentos em infraestrutura rodoviária no estímulo à expansão das grandes monoculturas agrícolas, soja e milho. Na sequência, fez-se uma caracterização do perfil socioeconômico da região de influência da rodovia BR 158, abrangendo demografia, fluxo de emprego, produção econômica, exportação e importação dos municípios, entre outros. Também identificou-se a repercussão dos investimentos em infraestrutura rodoviária nos municípios em questão, para os pequenos e médios segmentos industriais e comerciais e, para finalizar, identificaram-se as mercadorias que são transportadas e as condições de suporte da rodovia na perspectiva dos caminhoneiros. A metodologia utilizada, de natureza quanti-qualitativa, foi auxiliada por instrumentos, como: a observação, a entrevista, a pesquisa documental e bibliográfica, sendo os dados apresentados, em forma de comentário e de tabelas. Ao avaliar os impactos econômicos e sociais das transformações produtivas, na área do cerrado brasileiro, derivados das obras de infraestrutura de rodovias, esperou-se contribuir para explicar a natureza do processo de integração regional em Mato Grosso, no período atual, e projetá-lo para os próximos anos, com base nas obras de infraestrutura em questão