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1.
Genes Dev ; 34(7-8): 495-510, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32139423

RESUMO

Obesity-induced diabetes affects >400 million people worldwide. Uncontrolled lipolysis (free fatty acid release from adipocytes) can contribute to diabetes and obesity. To identify future therapeutic avenues targeting this pathway, we performed a high-throughput screen and identified the extracellular-regulated kinase 3 (ERK3) as a hit. We demonstrated that ß-adrenergic stimulation stabilizes ERK3, leading to the formation of a complex with the cofactor MAP kinase-activated protein kinase 5 (MK5), thereby driving lipolysis. Mechanistically, we identified a downstream target of the ERK3/MK5 pathway, the transcription factor FOXO1, which promotes the expression of the major lipolytic enzyme ATGL. Finally, we provide evidence that targeted deletion of ERK3 in mouse adipocytes inhibits lipolysis, but elevates energy dissipation, promoting lean phenotype and ameliorating diabetes. Thus, ERK3/MK5 represents a previously unrecognized signaling axis in adipose tissue and an attractive target for future therapies aiming to combat obesity-induced diabetes.


Assuntos
Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/fisiopatologia , Metabolismo Energético/genética , Lipólise/genética , Proteína Quinase 6 Ativada por Mitógeno/genética , Proteína Quinase 6 Ativada por Mitógeno/metabolismo , Obesidade/complicações , Células 3T3 , Tecido Adiposo/enzimologia , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Proteína Forkhead Box O1/metabolismo , Deleção de Genes , Células HEK293 , Humanos , Hipoglicemiantes/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lipase/genética , Lipase/metabolismo , Camundongos , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/genética
2.
Cell ; 144(5): 796-809, 2011 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-21333348

RESUMO

Interactions between bone and the reproductive system have until now been thought to be limited to the regulation of bone remodeling by the gonads. We now show that, in males, bone acts as a regulator of fertility. Using coculture assays, we demonstrate that osteoblasts are able to induce testosterone production by the testes, though they fail to influence estrogen production by the ovaries. Analyses of cell-specific loss- and gain-of-function models reveal that the osteoblast-derived hormone osteocalcin performs this endocrine function. By binding to a G protein-coupled receptor expressed in the Leydig cells of the testes, osteocalcin regulates in a CREB-dependent manner the expression of enzymes that is required for testosterone synthesis, promoting germ cell survival. This study expands the physiological repertoire of osteocalcin and provides the first evidence that the skeleton is an endocrine regulator of reproduction.


Assuntos
Osso e Ossos/fisiologia , Fertilidade , Osteocalcina/fisiologia , Animais , Células Cultivadas , Humanos , Células Intersticiais do Testículo/fisiologia , Masculino , Camundongos , Osteoblastos/fisiologia , Testículo/fisiologia
3.
Immunology ; 2024 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-38798068

RESUMO

Members of the Protein kinases D (PKD) family are described as regulators of T cell responses. From the two T cell-expressed isoforms PKD2 and PKD3, so far mainly the former was thoroughly investigated and is well understood. Recently, we have investigated also PKD3 using conventional as well as conditional T cell-specific knockout models. These studies suggested PKD3 to be a T cell-extrinsic regulator of the cells' fate. However, these former model systems did not take into account possible redundancies with the highly homologous PKD2. To overcome this issue and thus properly unravel PKD3's T cell-intrinsic functions, here we additionally used a mouse model overexpressing a constitutively active isoform of PKD3 specifically in the T cell compartment. These transgenic mice showed a slightly higher proportion of central memory T cells in secondary lymphoid organs and blood. This effect could not be explained via differences upon polyclonal stimulation in vitro, however, may be connected to the observed developmental aberrances in the CD8 single positive compartment during thymic development. Lastly, the observed alterations in the CD8+ T cell compartment did not impact proper immune response upon immunization with ovalbumin or in a subcutaneous tumour model suggesting only a small to absent biological relevance. Taking together the knowledge of all our published studies on PKD3 in the T cell compartment, we now conclude that T cell-intrinsic PKD3 is a fine-tuner of central memory T cell as well as CD8 single positive thymocyte development.

4.
Arch Biochem Biophys ; 751: 109825, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37992885

RESUMO

Extracellular signal-regulated kinase 3 (ERK3 also designated MAPK6 - mitogen-activated protein kinase 6) is a ubiquitously expressed kinase participating in the regulation of a broad spectrum of physiological and pathological processes. Targeted inhibition of the kinase may allow the development of novel treatment strategies for a variety of types of cancer and somatic pathologies, as well as preserving metabolic health, combat obesity and diabetes. We chose and synthesized three triazolo [4,5-d]pyrimidin-5-amines proposed previously as putative ERK3 inhibitors to assess their selectivity and biological effects in terms of metabolic state impact in living cells. As it was previously shown that ERK3 is a major regulator of lipolysis in adipocytes, we focused on this process. Our new results indicate that in addition to the previously identified lipolytic enzyme ATGL, ERK3 also regulates hormone-sensitive lipase (HSL) and monoglyceride lipase (MGL). Moreover, this kinase also promotes the abundance of fatty acid synthase (FASN) as well as protein kinase cAMP-activated catalytic subunit alpha (PKACα). To investigate various effects of putative ERK3 inhibitors on lipolysis, we utilized different adipocyte models. We demonstrated that molecules exhibit lipolysis-modulating effects; however, the effects of triazolo [4,5-d]pyrimidin-5-amines based inhibitors on lipolysis are not dependent on ERK3. Subsequently, we revealed a wide range of the compounds' possible targets using a machine learning-based prediction. Therefore, the tested compounds inhibit ERK3 in vitro, but the biological effect of this inhibition is significantly overlapped and modified by some other molecular events related to the non-selective binding to other targets.


Assuntos
Adipócitos , Lipólise
5.
Cell ; 136(2): 235-48, 2009 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-19135240

RESUMO

Dysfunction and loss of insulin-producing pancreatic beta cells represent hallmarks of diabetes mellitus. Here, we show that mice lacking the mitogen-activated protein kinase (MAPK) p38delta display improved glucose tolerance due to enhanced insulin secretion from pancreatic beta cells. Deletion of p38delta results in pronounced activation of protein kinase D (PKD), the latter of which we have identified as a pivotal regulator of stimulated insulin exocytosis. p38delta catalyzes an inhibitory phosphorylation of PKD1, thereby attenuating stimulated insulin secretion. In addition, p38delta null mice are protected against high-fat-feeding-induced insulin resistance and oxidative stress-mediated beta cell failure. Inhibition of PKD1 reverses enhanced insulin secretion from p38delta-deficient islets and glucose tolerance in p38delta null mice as well as their susceptibility to oxidative stress. In conclusion, the p38delta-PKD pathway integrates regulation of the insulin secretory capacity and survival of pancreatic beta cells, pointing to a pivotal role for this pathway in the development of overt diabetes mellitus.


Assuntos
Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Proteína Quinase 13 Ativada por Mitógeno/metabolismo , Proteína Quinase C/metabolismo , Animais , Exocitose , Feminino , Glucose/metabolismo , Complexo de Golgi/metabolismo , Secreção de Insulina , Masculino , Camundongos , Proteína Quinase 13 Ativada por Mitógeno/genética , Fosfolipases Tipo C/metabolismo
6.
EMBO J ; 37(22)2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30389661

RESUMO

Nutrient overload in combination with decreased energy dissipation promotes obesity and diabetes. Obesity results in a hormonal imbalance, which among others activates G protein-coupled receptors utilizing diacylglycerol (DAG) as secondary messenger. Protein kinase D1 (PKD1) is a DAG effector, which integrates multiple nutritional and hormonal inputs, but its physiological role in adipocytes is unknown. Here, we show that PKD1 promotes lipogenesis and suppresses mitochondrial fragmentation, biogenesis, respiration, and energy dissipation in an AMP-activated protein kinase (AMPK)-dependent manner. Moreover, mice lacking PKD1 in adipocytes are resistant to diet-induced obesity due to elevated energy expenditure. Beiging of adipocytes promotes energy expenditure and counteracts obesity. Consistently, deletion of PKD1 promotes expression of the ß3-adrenergic receptor (ADRB3) in a CCAAT/enhancer binding protein (C/EBP)-α- and δ-dependent manner, which leads to the elevated expression of beige markers in adipocytes and subcutaneous adipose tissue. Finally, deletion of PKD1 in adipocytes improves insulin sensitivity and ameliorates liver steatosis. Thus, depletion of PKD1 in adipocytes increases energy dissipation by several complementary mechanisms and might represent an attractive strategy to treat obesity and its related complications.


Assuntos
Adipócitos/metabolismo , Adiposidade , Metabolismo Energético , Fígado Gorduroso/metabolismo , Obesidade/metabolismo , Proteína Quinase C/metabolismo , Gordura Subcutânea/metabolismo , Células 3T3-L1 , Adipócitos/patologia , Animais , Proteína delta de Ligação ao Facilitador CCAAT/genética , Proteína delta de Ligação ao Facilitador CCAAT/metabolismo , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Mutantes , Obesidade/genética , Obesidade/patologia , Proteína Quinase C/genética , Receptores Adrenérgicos beta 3/genética , Receptores Adrenérgicos beta 3/metabolismo , Sistemas do Segundo Mensageiro/genética , Gordura Subcutânea/fisiologia
7.
Biochem Biophys Res Commun ; 612: 119-125, 2022 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-35523049

RESUMO

Kinases represent one of the largest druggable families of proteins. Importantly, many kinases are aberrantly activated/de-activated in multiple organs during obesity, which contributes to the development of diabetes and associated diseases. Previous results indicate that the complex between Extracellular-regulated kinase 3 (ERK3) and Mitogen-Activated Protein Kinase (MAPK)-activated protein kinase 5 (MK5) suppresses energy dissipation and promotes fatty acids (FAs) output in adipose tissue and, therefore promotes obesity and diabetes. However, the therapeutic potential of targeting this complex at the systemic level has not been fully explored. Here we applied a translational approach to target the ERK3/MK5 complex in mice. Importantly, deletion of ERK3 in the whole body or administration of MK5-specific inhibitor protects against obesity and promotes insulin sensitivity. Finally, we show that the expression of ERK3 and MK5 correlates with the degree of obesity and that ERK3/MK5 complex regulates energy dissipation in human adipocytes. Altogether, we demonstrate that ERK3/MK5 complex can be targeted in vivo to preserve metabolic health and combat obesity and diabetes.


Assuntos
Diabetes Mellitus , Proteínas Serina-Treonina Quinases , Animais , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos , Proteína Quinase 6 Ativada por Mitógeno/metabolismo , Obesidade
8.
Lipids Health Dis ; 19(1): 113, 2020 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-32466765

RESUMO

Protein kinase C (PKC) and Protein kinase D (PKD) isoforms can sense diacylglycerol (DAG) generated in the different cellular compartments in various physiological processes. DAG accumulates in multiple organs of the obese subjects, which leads to the disruption of metabolic homeostasis and the development of diabetes as well as associated diseases. Multiple studies proved that aberrant activation of PKCs and PKDs contributes to the development of metabolic diseases. DAG-sensing PKC and PKD isoforms play a crucial role in the regulation of metabolic homeostasis and therefore might serve as targets for the treatment of metabolic disorders such as obesity and diabetes.


Assuntos
Diglicerídeos/metabolismo , Glucose/metabolismo , Metabolismo dos Lipídeos , Proteína Quinase C/metabolismo , Animais , Diabetes Mellitus/etiologia , Diabetes Mellitus/metabolismo , Humanos , Insulina/metabolismo , Obesidade/etiologia , Obesidade/metabolismo , Transdução de Sinais
9.
Biochim Biophys Acta Mol Cell Res ; 1871(2): 119653, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38104800

RESUMO

Inappropriate lipid levels in the blood, as well as its content and composition in different organs, underlie multiple metabolic disorders including obesity, non-alcoholic fatty liver disease, type 2 diabetes, and atherosclerosis. Multiple processes contribute to the complex metabolism of triglycerides (TGs), fatty acids (FAs), and other lipid species. These consist of digestion and absorption of dietary lipids, de novo FAs synthesis (lipogenesis), uptake of TGs and FAs by peripheral tissues, TGs storage in the intracellular depots as well as lipid utilization for ß-oxidation and their conversion to lipid-derivatives. A majority of the enzymatic reactions linked to lipogenesis, TGs synthesis, lipid absorption, and transport are happening at the endoplasmic reticulum, while ß-oxidation takes place in mitochondria and peroxisomes. The Golgi apparatus is a central sorting, protein- and lipid-modifying organelle and hence is involved in lipid metabolism as well. However, the impact of the processes taking part in the Golgi apparatus are often overseen. The protein kinase D (PKD) family (composed of three members, PKD1, 2, and 3) is the master regulator of Golgi dynamics. PKDs are also a sensor of different lipid species in distinct cellular compartments. In this review, we discuss the roles of PKD family members in the regulation of lipid metabolism including the processes executed by PKDs at the Golgi apparatus. We also discuss the role of PKDs-dependent signaling in different cellular compartments and organs in the context of the development of metabolic disorders.


Assuntos
Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Proteína Quinase C/metabolismo , Complexo de Golgi/metabolismo , Triglicerídeos/metabolismo
10.
J Biol Chem ; 287(15): 12016-26, 2012 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-22337886

RESUMO

Disturbed Wnt signaling has been implicated in numerous diseases, including type 2 diabetes and the metabolic syndrome. In the present study, we have investigated cross-talk between insulin and Wnt signaling pathways using preadipocytes with and without knockdown of the Wnt co-receptors LRP5 and LRP6 and with and without knock-out of insulin and IGF-1 receptors. We find that Wnt stimulation leads to phosphorylation of insulin signaling key mediators, including Akt, GSK3ß, and ERK1/2, although with a lower fold stimulation and slower time course than observed for insulin. These Wnt effects are insulin/IGF-1 receptor-dependent and are lost in insulin/IGF-1 receptor double knock-out cells. Conversely, in LRP5 knockdown preadipocytes, insulin-induced phosphorylation of IRS1, Akt, GSK3ß, and ERK1/2 is highly reduced. This effect is specific to insulin, as compared with IGF-1, stimulation and appears to be due to an inducible interaction between LRP5 and the insulin receptor as demonstrated by co-immunoprecipitation. These data demonstrate that Wnt and insulin signaling pathways exhibit cross-talk at multiple levels. Wnt induces phosphorylation of Akt, ERK1/2, and GSK3ß, and this is dependent on insulin/IGF-1 receptors. Insulin signaling also involves the Wnt co-receptor LRP5, which has a positive effect on insulin signaling. Thus, altered Wnt and LRP5 activity can serve as modifiers of insulin action and insulin resistance in the pathophysiology of diabetes and metabolic syndrome.


Assuntos
Adipócitos/metabolismo , Insulina/fisiologia , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/fisiologia , Receptor Cross-Talk , Via de Sinalização Wnt , Células 3T3-L1 , Animais , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Imunoprecipitação , Insulina/metabolismo , Cinética , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Sistema de Sinalização das MAP Quinases , Camundongos , Fosforilação , Ligação Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Proteína Wnt3A/fisiologia , beta Catenina/metabolismo
11.
EMBO Mol Med ; 15(9): e16858, 2023 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-37490001

RESUMO

Hyperreactive platelets are commonly observed in diabetic patients indicating a potential link between glucose homeostasis and platelet reactivity. This raises the possibility that platelets may play a role in the regulation of metabolism. Pancreatic ß cells are the central regulators of systemic glucose homeostasis. Here, we show that factor(s) derived from ß cells stimulate platelet activity and platelets selectively localize to the vascular endothelium of pancreatic islets. Both depletion of platelets and ablation of major platelet adhesion or activation pathways consistently resulted in impaired glucose tolerance and decreased circulating insulin levels. Furthermore, we found platelet-derived lipid classes to promote insulin secretion and identified 20-Hydroxyeicosatetraenoic acid (20-HETE) as the main factor promoting ß cells function. Finally, we demonstrate that the levels of platelet-derived 20-HETE decline with age and that this parallels with reduced impact of platelets on ß cell function. Our findings identify an unexpected function of platelets in the regulation of insulin secretion and glucose metabolism, which promotes metabolic fitness in young individuals.


Assuntos
Células Secretoras de Insulina , Humanos , Secreção de Insulina , Insulina/metabolismo , Plaquetas , Glucose/metabolismo
13.
Dev Cell ; 12(6): 887-900, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17543862

RESUMO

Faithful cell-cycle progression is tightly controlled by the ubiquitin-proteasome system. Here we identify a human Cullin 3-based E3 ligase (Cul3) which is essential for mitotic division. In a complex with the substrate-specific adaptors KLHL9 and KLHL13, Cul3 is required for correct chromosome alignment in metaphase, proper midzone and midbody formation, and completion of cytokinesis. This Cul3-based E3 ligase removes components of the chromosomal passenger complex from mitotic chromosomes and allows their accumulation on the central spindle during anaphase. Aurora B directly binds to the substrate-recognition domain of KLHL9 and KLHL13 in vitro, and coimmunoprecipitates with the Cul3 complex during mitosis. Moreover, Aurora B is ubiquitylated in a Cul3-dependent manner in vivo, and by reconstituted Cul3/KLHL9/KLHL13 ligase in vitro. We thus propose that the Cul3/KLHL9/KLHL13 E3 ligase controls the dynamic behavior of Aurora B on mitotic chromosomes, and thereby coordinates faithful mitotic progression and completion of cytokinesis.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Cromossomos Humanos , Proteínas Culina/metabolismo , Citocinese , Mitose , Proteínas Serina-Treonina Quinases/metabolismo , Complexos Ubiquitina-Proteína Ligase/metabolismo , Aurora Quinase B , Aurora Quinases , Proteínas de Ciclo Celular/genética , Proteínas Culina/genética , Células HeLa , Humanos , Proteínas Serina-Treonina Quinases/genética , Fuso Acromático , Ubiquitina/metabolismo , Complexos Ubiquitina-Proteína Ligase/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
14.
EMBO Mol Med ; 14(5): e14742, 2022 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-35437952

RESUMO

The regular overconsumption of energy-dense foods (rich in lipids and sugars) results in elevated intestinal nutrient absorption and consequently excessive accumulation of lipids in the liver, adipose tissue, skeletal muscles, and other organs. This can eventually lead to obesity and obesity-associated diseases such as type 2 diabetes (T2D), non-alcoholic fatty liver disease (NAFLD), cardiovascular disease, and certain types of cancer, as well as aggravate inflammatory bowel disease (IBD). Therefore, targeting the pathways that regulate intestinal nutrient absorption holds significant therapeutic potential. In this review, we discuss the molecular and cellular mechanisms controlling intestinal lipid handling, their relevance to the development of metabolic diseases, and emerging therapeutic strategies.


Assuntos
Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Tecido Adiposo/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Lipídeos/uso terapêutico , Fígado/metabolismo , Obesidade/metabolismo
15.
Life Sci Alliance ; 4(8)2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34145024

RESUMO

Members of the protein kinase D (PKD) family (PKD1, 2, and 3) integrate hormonal and nutritional inputs to regulate complex cellular metabolism. Despite the fact that a number of functions have been annotated to particular PKDs, their molecular targets are relatively poorly explored. PKD3 promotes insulin sensitivity and suppresses lipogenesis in the liver of animals fed a high-fat diet. However, its substrates are largely unknown. Here we applied proteomic approaches to determine PKD3 targets. We identified more than 300 putative targets of PKD3. Furthermore, biochemical analysis revealed that PKD3 regulates cAMP-dependent PKA activity, a master regulator of the hepatic response to glucagon and fasting. PKA regulates glucose, lipid, and amino acid metabolism in the liver, by targeting key enzymes in the respective processes. Among them the PKA targets phenylalanine hydroxylase (PAH) catalyzes the conversion of phenylalanine to tyrosine. Consistently, we showed that PKD3 is activated by glucagon and promotes glucose and tyrosine levels in hepatocytes. Therefore, our data indicate that PKD3 might play a role in the hepatic response to glucagon.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Glucagon/farmacologia , Hepatócitos/citologia , Proteína Quinase C/metabolismo , Proteômica/métodos , Animais , Células Cultivadas , Jejum , Glucose/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Camundongos , Fenilalanina Hidroxilase/metabolismo , Fosforilação , Cultura Primária de Células , Mapas de Interação de Proteínas , Tirosina/metabolismo
16.
Sci Rep ; 11(1): 1979, 2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-33479343

RESUMO

Paternal obesity is known to have a negative impact on the male's reproductive health as well as the health of his offspring. Although epigenetic mechanisms have been implicated in the non-genetic transmission of acquired traits, the effect of paternal obesity on gene expression in the preimplantation embryo has not been fully studied. To this end, we investigated whether paternal obesity is associated with gene expression changes in eight-cell stage embryos fathered by males on a high-fat diet. We used single embryo RNA-seq to compare the gene expression profile of embryos generated by males on a high fat (HFD) versus control (CD) diet. This analysis revealed significant upregulation of the Samd4b and Gata6 gene in embryos in response to a paternal HFD. Furthermore, we could show a significant increase in expression of both Gata6 and Samd4b during differentiation of stromal vascular cells into mature adipocytes. These findings suggest that paternal obesity may induce changes in the male germ cells which are associated with the gene expression changes in the resulting preimplantation embryos.


Assuntos
Epigênese Genética , Fator de Transcrição GATA6/genética , Obesidade/genética , Proteínas Repressoras/genética , Transcriptoma/genética , Animais , Blastocisto/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Embrião de Mamíferos , Desenvolvimento Embrionário/genética , Pai , Regulação da Expressão Gênica/genética , Genoma Humano/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Obesidade/patologia , RNA-Seq
17.
EMBO Mol Med ; 13(5): e13548, 2021 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-33949105

RESUMO

Lipids are the most energy-dense components of the diet, and their overconsumption promotes obesity and diabetes. Dietary fat content has been linked to the lipid processing activity by the intestine and its overall capacity to absorb triglycerides (TG). However, the signaling cascades driving intestinal lipid absorption in response to elevated dietary fat are largely unknown. Here, we describe an unexpected role of the protein kinase D2 (PKD2) in lipid homeostasis. We demonstrate that PKD2 activity promotes chylomicron-mediated TG transfer in enterocytes. PKD2 increases chylomicron size to enhance the TG secretion on the basolateral side of the mouse and human enterocytes, which is associated with decreased abundance of APOA4. PKD2 activation in intestine also correlates positively with circulating TG in obese human patients. Importantly, deletion, inactivation, or inhibition of PKD2 ameliorates high-fat diet-induced obesity and diabetes and improves gut microbiota profile in mice. Taken together, our findings suggest that PKD2 represents a key signaling node promoting dietary fat absorption and may serve as an attractive target for the treatment of obesity.


Assuntos
Quilomícrons , Metabolismo dos Lipídeos , Animais , Quilomícrons/metabolismo , Humanos , Intestinos , Camundongos , Obesidade , Proteína Quinase D2 , Proteínas Quinases , Triglicerídeos
18.
Biomolecules ; 10(9)2020 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-32872540

RESUMO

The family of mitogen-activated protein kinases (MAPKs) consists of fourteen members and has been implicated in regulation of virtually all cellular processes. MAPKs are divided into two groups, conventional and atypical MAPKs. Conventional MAPKs are further classified into four sub-families: extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK1, 2 and 3), p38 (α, ß, γ, δ), and extracellular signal-regulated kinase 5 (ERK5). Four kinases, extracellular signal-regulated kinase 3, 4, and 7 (ERK3, 4 and 7) as well as Nemo-like kinase (NLK) build a group of atypical MAPKs, which are activated by different upstream mechanisms than conventional MAPKs. Early studies identified JNK1/2 and ERK1/2 as well as p38α as a central mediators of inflammation-evoked insulin resistance. These kinases have been also implicated in the development of obesity and diabetes. Recently, other members of conventional MAPKs emerged as important mediators of liver, skeletal muscle, adipose tissue, and pancreatic ß-cell metabolism. Moreover, latest studies indicate that atypical members of MAPK family play a central role in the regulation of adipose tissue function. In this review, we summarize early studies on conventional MAPKs as well as recent findings implicating previously ignored members of the MAPK family. Finally, we discuss the therapeutic potential of drugs targeting specific members of the MAPK family.


Assuntos
Doenças Metabólicas/enzimologia , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Animais , Humanos , MAP Quinase Quinase 4/metabolismo , Sistema de Sinalização das MAP Quinases , Proteína Quinase 7 Ativada por Mitógeno/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
19.
Sci Signal ; 12(593)2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31387939

RESUMO

Hepatic activation of protein kinase C (PKC) isoforms by diacylglycerol (DAG) promotes insulin resistance and contributes to the development of type 2 diabetes (T2D). The closely related protein kinase D (PKD) isoforms act as effectors for DAG and PKC. Here, we showed that PKD3 was the predominant PKD isoform expressed in hepatocytes and was activated by lipid overload. PKD3 suppressed the activity of downstream insulin effectors including the kinase AKT and mechanistic target of rapamycin complex 1 and 2 (mTORC1 and mTORC2). Hepatic deletion of PKD3 in mice improved insulin-induced glucose tolerance. However, increased insulin signaling in the absence of PKD3 promoted lipogenesis mediated by SREBP (sterol regulatory element-binding protein) and consequently increased triglyceride and cholesterol content in the livers of PKD3-deficient mice fed a high-fat diet. Conversely, hepatic-specific overexpression of a constitutively active PKD3 mutant suppressed insulin-induced signaling and caused insulin resistance. Our results indicate that PKD3 provides feedback on hepatic lipid production and suppresses insulin signaling. Therefore, manipulation of PKD3 activity could be used to decrease hepatic lipid content or improve hepatic insulin sensitivity.


Assuntos
Colesterol/biossíntese , Hepatócitos/metabolismo , Insulina/metabolismo , Proteína Quinase C/metabolismo , Transdução de Sinais , Triglicerídeos/biossíntese , Animais , Colesterol/genética , Insulina/genética , Lipogênese/genética , Camundongos , Camundongos Transgênicos , Proteína Quinase C/genética , Triglicerídeos/genética
20.
Sci Rep ; 7(1): 7191, 2017 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-28775290

RESUMO

Adipocytes play a central role in maintaining metabolic homeostasis in the body. Differentiation of adipocyte precursor cells requires the transcriptional activity of peroxisome proliferator-activated receptor-γ (Pparγ) and CCAAT/enhancer binding proteins (C/Ebps). Transcriptional activity is regulated by signaling modules activated by a plethora of hormones and nutrients. Mechanistic target of rapamacin complexes (mTORC) 1 and 2 are central for the coordination of hormonal and nutritional inputs in cells and are essential for adipogenesis. Serum glucocorticoid kinase 1 (Sgk1)-dependent phosphorylation of N-Myc downstream-regulated gene 1 (Ndrg1) is a hallmark of mTORC2 activation in cells. Moreover, Pparγ activation promotes Ndrg1 expression. However, the impact of Ndrg1 on adipocyte differentiation and function has not yet been defined. Here, we show that Ndrg1 expression and its Sgk1-dependent phosphorylation are induced during adipogenesis. Consistently, we demonstrate that Ndrg1 promotes adipocyte differentiation and function by inducing Pparγ expression. Additionally, our results indicate that Ndrg1 is required for C/Ebpα phosphorylation. Moreover, we found that Ndrg1 phosphorylation by Sgk1 promotes adipocyte formation. Taken together, we show that induction of Ndrg1 expression by Pparγ and its phosphorylation by Sgk1 kinase are required for the acquisition of adipocyte characteristics by precursor cells.


Assuntos
Adipócitos/citologia , Adipócitos/metabolismo , Adipogenia/genética , Proteínas de Ciclo Celular/genética , Diferenciação Celular/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Células 3T3-L1 , Animais , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Proteínas de Ciclo Celular/metabolismo , Expressão Gênica , Técnicas de Silenciamento de Genes , Proteínas Imediatamente Precoces/metabolismo , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Metabolismo dos Lipídeos , Camundongos , Mutação , PPAR gama/metabolismo , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , RNA Interferente Pequeno/genética
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