7 results on '"Guo DF"'
Search Results
2. The BBSome regulates mitochondria dynamics and function.
- Author
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Guo DF, Merrill RA, Qian L, Hsu Y, Zhang Q, Lin Z, Thedens DR, Usachev YM, Grumbach I, Sheffield VC, Strack S, and Rahmouni K
- Subjects
- Mice, Animals, Obesity metabolism, Proteins, Cell Line, Mitochondria metabolism, Bardet-Biedl Syndrome genetics, Bardet-Biedl Syndrome metabolism
- Abstract
Objective: The essential role of mitochondria in regulation of metabolic function and other physiological processes has garnered enormous interest in understanding the mechanisms controlling the function of this organelle. We assessed the role of the BBSome, a protein complex composed of eight Bardet-Biedl syndrome (BBS) proteins, in the control of mitochondria dynamic and function., Methods: We used a multidisciplinary approach that include CRISPR/Cas9 technology-mediated generation of a stable Bbs1 gene knockout hypothalamic N39 neuronal cell line. We also analyzed the phenotype of BBSome deficient mice in presence or absence of the gene encoding A-kinase anchoring protein 1 (AKAP1)., Results: Our data show that the BBSome play an important role in the regulation of mitochondria dynamics and function. Disruption of the BBSome cause mitochondria hyperfusion in cell lines, fibroblasts derived from patients as well as in hypothalamic neurons and brown adipocytes of mice. The morphological changes in mitochondria translate into functional abnormalities as indicated by the reduced oxygen consumption rate and altered mitochondrial distribution and calcium handling. Mechanistically, we demonstrate that the BBSome modulates the activity of dynamin-like protein 1 (DRP1), a key regulator of mitochondrial fission, by regulating its phosphorylation and translocation to the mitochondria. Notably, rescuing the decrease in DRP1 activity through deletion of one copy of the gene encoding AKAP1 was effective to normalize the defects in mitochondrial morphology and activity induced by BBSome deficiency. Importantly, this was associated with improvement in several of the phenotypes caused by loss of the BBSome such as the neuroanatomical abnormalities, metabolic alterations and obesity highlighting the importance of mitochondria defects in the pathophysiology of BBS., Conclusions: These findings demonstrate a critical role of the BBSome in the modulation of mitochondria function and point to mitochondrial defects as a key disease mechanism in BBS., (Copyright © 2022 The Author(s). Published by Elsevier GmbH.. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
3. Obesity induces resistance to central action of BMP8B through a mechanism involving the BBSome.
- Author
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Rial-Pensado E, Freire-Agulleiro O, Ríos M, Guo DF, Contreras C, Seoane-Collazo P, Tovar S, Nogueiras R, Diéguez C, Rahmouni K, and López M
- Subjects
- Adipose Tissue, White metabolism, Animals, Mice, Obesity metabolism, Rats, Adipose Tissue, Brown metabolism, Bone Morphogenetic Proteins metabolism, Thermogenesis physiology
- Abstract
Objective: Bone morphogenetic protein 8B (BMP8B) plays a major role in the regulation of energy homeostasis by modulating brown adipose tissue (BAT) thermogenesis and white adipose tissue (WAT) browning. Here, we investigated whether BMP8B's role in metabolism is affected by obesity and the possible molecular mechanisms underlying that action., Methods: Central treatments with BMP8B were performed in rats fed a standard (SD) and high-fat diet (HFD), as well as in genetically modified mice. Energy balance studies, infrared thermographic analysis of BAT and molecular analysis of the hypothalamus, BAT and WAT were carried out., Results: We show for the first time that HFD-induced obesity elicits resistance to the central actions of BMP8B on energy balance. This obesity-induced BMP8B resistance is explained by i) lack of effects on AMP-activated protein kinase (AMPK) signaling, ii) decreased BMP receptors signaling and iii) reduced expression of Bardet-Biedl Syndrome 1 (BBS1) protein, a key component of the protein complex BBSome in the ventromedial nucleus of the hypothalamus (VMH). The possible mechanistic involvement of BBS1 in this process is demonstrated by lack of a central response to BMP8B in mice carrying a single missense disease-causing mutation in the Bbs1 gene., Conclusions: Overall, our data uncover a new mechanism of central resistance to hormonal action that may be of relevance in the pathophysiology of obesity., (Copyright © 2022 The Author(s). Published by Elsevier GmbH.. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
4. Endothelial BBSome is essential for vascular, metabolic, and retinal functions.
- Author
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Jiang J, Reho JJ, Bhattarai S, Cherascu I, Hedberg-Buenz A, Meyer KJ, Tayyari F, Rauckhorst AJ, Guo DF, Morgan DA, Taylor EB, Anderson MG, Drack AV, and Rahmouni K
- Subjects
- Animals, Body Weight, Female, Male, Mice, Mice, Congenic, Mice, Inbred C57BL, Mice, Transgenic, Endothelial Cells metabolism, Microtubule-Associated Proteins metabolism, Retina metabolism
- Abstract
Objectives: Endothelial cells that line the entire vascular system play a pivotal role in the control of various physiological processes, including metabolism. Additionally, endothelial dysfunction is associated with many pathological conditions, including obesity. Here, we assessed the role of the BBSome, a protein complex composed of eight Bardet-Biedl syndrome (BBS) proteins in endothelial cells., Methods: We studied the effects of BBSome disruption in endothelial cells on vascular function, body weight, glucose homeostasis, and the liver and retina. For this, we generated mice with selective BBSome disruption in endothelial cells through Bbs1 gene deletion., Results: We found that endothelial cell-specific BBSome disruption causes endothelial dysfunction, as indicated by the impaired acetylcholine-induced vasorelaxation in both the aorta and mesenteric artery. This was associated with an increase in the contractile response to thromboxane A2 receptor agonist (U46619) in the mesenteric artery. Mechanistically, we demonstrated that mice lacking the Bbs1 gene in endothelial cells show elevated vascular angiotensinogen gene expression, implicating renin-angiotensin system activation in the vascular changes evoked by endothelial BBSome deficiency. Strikingly, our data indicate that endothelial BBSome deficiency increases body weight and fat mass and causes hepatosteatosis along with alterations in hepatic expression of lipid metabolism-related genes and metabolomics profile. In addition, electroretinogram and optical coherence tomography analyses revealed functional and structural abnormalities in the retina, evoked by absence of the endothelial BBSome., Conclusions: Our findings demonstrate that the BBSome in endothelial cells is required for the regulation of vascular function, adiposity, hepatic lipid metabolism, and retinal function., (Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
5. BBSome ablation in SF1 neurons causes obesity without comorbidities.
- Author
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Rouabhi M, Guo DF, Morgan DA, Zhu Z, López M, Zingman L, Grobe JL, and Rahmouni K
- Subjects
- Adipose Tissue, Brown metabolism, Adipose Tissue, White metabolism, Adiposity genetics, Animals, Body Weight genetics, Comorbidity, Energy Intake genetics, Energy Metabolism genetics, Female, Integrases metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Obesity genetics, Promoter Regions, Genetic, RNA Splicing Factors genetics, Ventromedial Hypothalamic Nucleus metabolism, Gene Deletion, Microtubule-Associated Proteins genetics, Microtubule-Associated Proteins metabolism, Neurons metabolism, Obesity metabolism, RNA Splicing Factors metabolism, Signal Transduction genetics
- Abstract
Objectives: The hypothalamic ventromedial nucleus (VMH) plays a major role in metabolic control, but the molecular mechanisms involved remain poorly defined. We analyzed the relevance of the BBSome, a protein complex composed of 8 Bardet-Biedl syndrome (BBS) proteins including BBS1, in VMH steroidogenic factor 1 (SF1) neurons for the control of energy homeostasis and related physiological processes., Methods: We generated mice bearing selective BBSome disruption, through Bbs1 gene deletion, in SF1 neurons (SF1
Cre /Bbs1fl/fl ). We analyzed the consequence on body weight, glucose homeostasis, and cardiovascular autonomic function of BBSome loss in SF1 neurons., Results: SF1Cre /Bbs1fl/fl mice had increased body weight and adiposity under normal chow conditions. Food intake, energy absorption, and digestive efficiency were not altered by Bbs1 gene deletion in SF1 neurons. SF1Cre /Bbs1fl/fl mice exhibited lower energy expenditure, particularly during the dark cycle. Consistent with this finding, SF1Cre /Bbs1fl/fl mice displayed reduced sympathetic nerve traffic and expression of markers of thermogenesis in brown adipose tissue. SF1Cre /Bbs1fl/fl mice also had lower sympathetic nerve activity to subcutaneous white adipose tissue that was associated with a protein expression profile that promotes lipid accumulation. Notably, despite obesity and hyperinsulinemia, SF1Cre /Bbs1fl/fl mice did not exhibit significant changes in glucose metabolism, insulin sensitivity, blood pressure, and baroreflex sensitivity., Conclusions: Our findings demonstrate that the SF1 neuron BBSome is necessary for the regulation of energy homeostasis through modulation of the activity of the sympathetic nervous system and that the SF1 neuron BBSome is required for the development of obesity-related comorbidities., (Copyright © 2021 The Authors. Published by Elsevier GmbH.. All rights reserved.)- Published
- 2021
- Full Text
- View/download PDF
6. Corrigendum to "Differential contribution of POMC and AgRP neurons to the regulation of regional autonomic nerve activity by leptin" [Molecular Metabolism 8 (2018) 1-12].
- Author
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Bell BB, Harlan SM, Morgan DA, Guo DF, Cui H, and Rahmouni K
- Published
- 2018
- Full Text
- View/download PDF
7. Differential contribution of POMC and AgRP neurons to the regulation of regional autonomic nerve activity by leptin.
- Author
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Bell BB, Harlan SM, Morgan DA, Guo DF, Cui H, and Rahmouni K
- Subjects
- Adipose Tissue, Brown metabolism, Agouti-Related Protein genetics, Animals, Autonomic Nervous System cytology, Autonomic Nervous System metabolism, Female, Male, Mice, Mice, Inbred C57BL, Neurons physiology, Phosphatidylinositol 3-Kinases genetics, Phosphatidylinositol 3-Kinases metabolism, Pro-Opiomelanocortin genetics, Receptors, Leptin genetics, Receptors, Leptin metabolism, Agouti-Related Protein metabolism, Autonomic Nervous System physiology, Leptin metabolism, Neurons metabolism, Pro-Opiomelanocortin metabolism
- Abstract
Objectives: The autonomic nervous system is critically involved in mediating the control by leptin of many physiological processes. Here, we examined the role of the leptin receptor (LepR) in proopiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons in mediating the effects of leptin on regional sympathetic and parasympathetic nerve activity., Methods: We analyzed how deletion of the LepR in POMC neurons (POMC
Cre /LepRfl/fl mice) or AgRP neurons (AgRPCre /LepRfl/fl mice) affects the ability of leptin to increase sympathetic and parasympathetic nerve activity. We also studied mice lacking the catalytic p110α or p110β subunits of phosphatidylinositol-3 kinase (PI3K) in POMC neurons., Results: Leptin-evoked increase in sympathetic nerve activity subserving thermogenic brown adipose tissue was partially blunted in mice lacking the LepR in either POMC or AgRP neurons. On the other hand, loss of the LepR in AgRP, but not POMC, neurons interfered with leptin-induced sympathetic nerve activation to the inguinal fat depot. The increase in hepatic sympathetic traffic induced by leptin was also reduced in mice lacking the LepR in AgRP, but not POMC, neurons whereas LepR deletion in either AgRP or POMC neurons attenuated the hepatic parasympathetic nerve activation evoked by leptin. Interestingly, the renal, lumbar and splanchnic sympathetic nerve activation caused by leptin were significantly blunted in POMCCre /LepRfl/fl mice, but not in AgRPCre /LepRfl/fl mice. However, loss of the LepR in POMC or AgRP neurons did not interfere with the ability of leptin to increase sympathetic traffic to the adrenal gland. Furthermore, ablation of the p110α, but not the p110β, isoform of PI3K from POMC neurons eliminated the leptin-elicited renal sympathetic nerve activation. Finally, we show trans-synaptic retrograde tracing of both POMC and AgRP neurons from the kidneys., Conclusions: POMC and AgRP neurons are differentially involved in mediating the effects of leptin on autonomic nerve activity subserving various tissues and organs., (Copyright © 2017 The Authors. Published by Elsevier GmbH.. All rights reserved.)- Published
- 2018
- Full Text
- View/download PDF
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