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1.
Nat Commun ; 12(1): 4829, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376643

RESUMO

Plasma hyaluronan (HA) increases systemically in type 2 diabetes (T2D) and the HA synthesis inhibitor, 4-Methylumbelliferone, has been proposed to treat the disease. However, HA is also implicated in normal physiology. Therefore, we generated a Hyaluronan Synthase 2 transgenic mouse line, driven by a tet-response element promoter to understand the role of HA in systemic metabolism. To our surprise, adipocyte-specific overproduction of HA leads to smaller adipocytes and protects mice from high-fat-high-sucrose-diet-induced obesity and glucose intolerance. Adipocytes also have more free glycerol that can be released upon beta3 adrenergic stimulation. Improvements in glucose tolerance were not linked to increased plasma HA. Instead, an HA-driven systemic substrate redistribution and adipose tissue-liver crosstalk contributes to the systemic glucose improvements. In summary, we demonstrate an unexpected improvement in glucose metabolism as a consequence of HA overproduction in adipose tissue, which argues against the use of systemic HA synthesis inhibitors to treat obesity and T2D.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Dioxóis/farmacologia , Glucose/metabolismo , Ácido Hialurônico/metabolismo , Lipólise/efeitos dos fármacos , Adipócitos/citologia , Tecido Adiposo/citologia , Animais , Células Cultivadas , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica/efeitos adversos , Feminino , Intolerância à Glucose/metabolismo , Homeostase , Humanos , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Camundongos Transgênicos , Obesidade/etiologia , Obesidade/metabolismo
2.
Nat Metab ; 3(7): 890-891, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34211181
3.
Am J Physiol Endocrinol Metab ; 321(1): E146-E155, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34097543

RESUMO

Cannabinoid 1 receptor (CB1R) inverse agonists reduce body weight and improve several parameters of glucose homeostasis. However, these drugs have also been associated with deleterious side effects. CB1R expression is widespread in the brain and in peripheral tissues, but whether specific sites of expression can mediate the beneficial metabolic effects of CB1R drugs, while avoiding the untoward side effects, remains unclear. Evidence suggests inverse agonists may act on key sites within the central nervous system to improve metabolism. The ventromedial hypothalamus (VMH) is a critical node regulating energy balance and glucose homeostasis. To determine the contributions of CB1Rs expressed in VMH neurons in regulating metabolic homeostasis, we generated mice lacking CB1Rs in the VMH. We found that the deletion of CB1Rs in the VMH did not affect body weight in chow- and high-fat diet-fed male and female mice. We also found that deletion of CB1Rs in the VMH did not alter weight loss responses induced by the CB1R inverse agonist SR141716. However, we did find that CB1Rs of the VMH regulate parameters of glucose homeostasis independent of body weight in diet-induced obese male mice.NEW & NOTEWORTHY Cannabinoid 1 receptors (CB1Rs) regulate metabolic homeostasis, and CB1R inverse agonists reduce body weight and improve parameters of glucose metabolism. However, the cell populations expressing CB1Rs that regulate metabolic homeostasis remain unclear. CB1Rs are highly expressed in the ventromedial hypothalamic nucleus (VMH), which is a crucial node that regulates metabolism. With CRISPR/Cas9, we generated mice lacking CB1Rs specifically in VMH neurons and found that CB1Rs in VMH neurons are essential for the regulation of glucose metabolism independent of body weight regulation.


Assuntos
Peso Corporal/fisiologia , Glucose/metabolismo , Homeostase/fisiologia , Neurônios/metabolismo , Receptor CB1 de Canabinoide/fisiologia , Núcleo Hipotalâmico Ventromedial/metabolismo , Animais , Composição Corporal/fisiologia , Proteína 9 Associada à CRISPR , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Dieta Hiperlipídica , Metabolismo Energético/fisiologia , Feminino , Edição de Genes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/etiologia , Obesidade/metabolismo , Receptor CB1 de Canabinoide/deficiência , Receptor CB1 de Canabinoide/genética
4.
Nat Commun ; 12(1): 3320, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34083525

RESUMO

Exposure of mice or humans to cold promotes significant changes in brown adipose tissue (BAT) with respect to histology, lipid content, gene expression, and mitochondrial mass and function. Herein we report that the lipid droplet coat protein Perilipin 5 (PLIN5) increases markedly in BAT during exposure of mice to cold. To understand the functional significance of cold-induced PLIN5, we created and characterized gain- and loss-of-function mouse models. Enforcing PLIN5 expression in mouse BAT mimics the effects of cold with respect to mitochondrial cristae packing and uncoupled substrate-driven respiration. PLIN5 is necessary for the maintenance of mitochondrial cristae structure and respiratory function during cold stress. We further show that promoting PLIN5 function in BAT is associated with healthy remodeling of subcutaneous white adipose tissue and improvements in systemic glucose tolerance and diet-induced hepatic steatosis. These observations will inform future strategies that seek to exploit thermogenic adipose tissue as a therapeutic target for type 2 diabetes, obesity, and nonalcoholic fatty liver disease.


Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Mitocôndrias/metabolismo , Perilipina-5/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Animais , Temperatura Baixa/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Dioxóis/farmacologia , Glucose/metabolismo , Humanos , Resistência à Insulina , Lipase/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitocôndrias/ultraestrutura , Modelos Biológicos , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Perilipina-5/deficiência , Perilipina-5/genética , Sirtuína 1/metabolismo , Termogênese/genética , Proteína Desacopladora 1/deficiência , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo , Regulação para Cima
5.
Trends Endocrinol Metab ; 32(8): 537-539, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33972177

RESUMO

Although cellular heterogeneity has been described for metabolic pathways, the upstream mechanisms, the downstream consequences, and the flexibility and transmission of these preferences to daughter cells remains largely unknown. Using live-cell imaging, Kosaisawe et al. demonstrate that cellular metabolism, determined by glycolysis and ATP, is spontaneously heterogeneous, plastic, and regulatory.

6.
Nat Rev Cardiol ; 18(10): 701-711, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33772258

RESUMO

Increases in calorie consumption and sedentary lifestyles are fuelling a global pandemic of cardiometabolic diseases, including coronary artery disease, diabetes mellitus, cardiomyopathy and heart failure. These lifestyle factors, when combined with genetic predispositions, increase the levels of circulating lipids, which can accumulate in non-adipose tissues, including blood vessel walls and the heart. The metabolism of these lipids produces bioactive intermediates that disrupt cellular function and survival. A compelling body of evidence suggests that sphingolipids, such as ceramides, account for much of the tissue damage in these cardiometabolic diseases. In humans, serum ceramide levels are proving to be accurate biomarkers of adverse cardiovascular disease outcomes. In mice and rats, pharmacological inhibition or depletion of enzymes driving de novo ceramide synthesis prevents the development of diabetes, atherosclerosis, hypertension and heart failure. In cultured cells and isolated tissues, ceramides perturb mitochondrial function, block fuel usage, disrupt vasodilatation and promote apoptosis. In this Review, we discuss the body of literature suggesting that ceramides are drivers - and not merely passengers - on the road to cardiovascular disease. Moreover, we explore the feasibility of therapeutic strategies to lower ceramide levels to improve cardiovascular health.

7.
J Clin Endocrinol Metab ; 106(8): e3098-e3109, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-33705551

RESUMO

CONTEXT: Genome-wide association studies have identified associations between a common single nucleotide polymorphism (SNP; rs267738) in CERS2, a gene that encodes a (dihydro)ceramide synthase that is involved in the biosynthesis of very-long-chain sphingolipids (eg, C20-C26) and indices of metabolic dysfunction (eg, impaired glucose homeostasis). However, the biological consequences of this mutation on enzyme activity and its causal roles in metabolic disease are unresolved. OBJECTIVE: The studies described herein aimed to characterize the effects of rs267738 on CERS2 enzyme activity, sphingolipid profiles, and metabolic outcomes. DESIGN: We performed in-depth lipidomic and metabolic characterization of a novel CRISPR knock-in mouse modeling the rs267738 variant. In parallel, we conducted mass spectrometry-based, targeted lipidomics on 567 serum samples collected through the Utah Coronary Artery Disease study, which included 185 patients harboring 1 (n = 163) or both (n = 22) rs267738 alleles. RESULTS: In-silico analysis of the amino acid substitution within CERS2 caused by the rs267738 mutation suggested that rs267738 is deleterious for enzyme function. Homozygous knock-in mice had reduced liver CERS2 activity and enhanced diet-induced glucose intolerance and hepatic steatosis. However, human serum sphingolipids and a ceramide-based cardiac event risk test 1 score of cardiovascular disease were not significantly affected by rs267738 allele count. CONCLUSIONS: The rs267738 SNP leads to a partial loss-of-function of CERS2, which worsened metabolic parameters in knock-in mice. However, rs267738 was insufficient to effect changes in serum sphingolipid profiles in subjects from the Utah Coronary Artery Disease Study.

8.
Proc Natl Acad Sci U S A ; 118(9)2021 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-33619103

RESUMO

We evaluated the potential for a monoclonal antibody antagonist of the glucagon receptor (Ab-4) to maintain glucose homeostasis in type 1 diabetic rodents. We noted durable and sustained improvements in glycemia which persist long after treatment withdrawal. Ab-4 promoted ß-cell survival and enhanced the recovery of insulin+ islet mass with concomitant increases in circulating insulin and C peptide. In PANIC-ATTAC mice, an inducible model of ß-cell apoptosis which allows for robust assessment of ß-cell regeneration following caspase-8-induced diabetes, Ab-4 drove a 6.7-fold increase in ß-cell mass. Lineage tracing suggests that this restoration of functional insulin-producing cells was at least partially driven by α-cell-to-ß-cell conversion. Following hyperglycemic onset in nonobese diabetic (NOD) mice, Ab-4 treatment promoted improvements in C-peptide levels and insulin+ islet mass was dramatically increased. Lastly, diabetic mice receiving human islet xenografts showed stable improvements in glycemic control and increased human insulin secretion.


Assuntos
Anticorpos Monoclonais/farmacologia , Diabetes Mellitus Experimental/terapia , Células Secretoras de Glucagon/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Receptores de Glucagon/antagonistas & inibidores , Animais , Glicemia/metabolismo , Peptídeo C/metabolismo , Linhagem da Célula/efeitos dos fármacos , Transdiferenciação Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 1/terapia , Expressão Gênica , Glucagon/antagonistas & inibidores , Glucagon/metabolismo , Células Secretoras de Glucagon/metabolismo , Células Secretoras de Glucagon/patologia , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/fisiologia , Transplante das Ilhotas Pancreáticas , Camundongos , Camundongos Endogâmicos NOD , Tamanho do Órgão/efeitos dos fármacos , Receptores de Glucagon/genética , Receptores de Glucagon/metabolismo , Resultado do Tratamento
9.
J Clin Invest ; 131(8)2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33591957

RESUMO

Aberrant lipid metabolism promotes the development of skeletal muscle insulin resistance, but the exact identity of lipid-mediated mechanisms relevant to human obesity remains unclear. A comprehensive lipidomic analysis of primary myocytes from individuals who were insulin-sensitive and lean (LN) or insulin-resistant with obesity (OB) revealed several species of lysophospholipids (lyso-PLs) that were differentially abundant. These changes coincided with greater expression of lysophosphatidylcholine acyltransferase 3 (LPCAT3), an enzyme involved in phospholipid transacylation (Lands cycle). Strikingly, mice with skeletal muscle-specific knockout of LPCAT3 (LPCAT3-MKO) exhibited greater muscle lysophosphatidylcholine/phosphatidylcholine, concomitant with improved skeletal muscle insulin sensitivity. Conversely, skeletal muscle-specific overexpression of LPCAT3 (LPCAT3-MKI) promoted glucose intolerance. The absence of LPCAT3 reduced phospholipid packing of cellular membranes and increased plasma membrane lipid clustering, suggesting that LPCAT3 affects insulin receptor phosphorylation by modulating plasma membrane lipid organization. In conclusion, obesity accelerates the skeletal muscle Lands cycle, whose consequence might induce the disruption of plasma membrane organization that suppresses muscle insulin action.


Assuntos
Membrana Celular/metabolismo , Resistência à Insulina , Metabolismo dos Lipídeos , Lisofosfolipídeos/metabolismo , Músculo Esquelético/metabolismo , 1-Acilglicerofosfocolina O-Aciltransferase/genética , 1-Acilglicerofosfocolina O-Aciltransferase/metabolismo , Acilação , Animais , Membrana Celular/genética , Membrana Celular/patologia , Células Cultivadas , Humanos , Lisofosfolipídeos/genética , Camundongos , Camundongos Knockout , Músculo Esquelético/patologia , Fosforilação/genética , Receptor de Insulina/genética , Receptor de Insulina/metabolismo
10.
Cell Metab ; 33(3): 629-648.e10, 2021 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-33333007

RESUMO

The metabolic rewiring of cardiomyocytes is a widely accepted hallmark of heart failure (HF). These metabolic changes include a decrease in mitochondrial pyruvate oxidation and an increased export of lactate. We identify the mitochondrial pyruvate carrier (MPC) and the cellular lactate exporter monocarboxylate transporter 4 (MCT4) as pivotal nodes in this metabolic axis. We observed that cardiac assist device-induced myocardial recovery in chronic HF patients was coincident with increased myocardial expression of the MPC. Moreover, the genetic ablation of the MPC in cultured cardiomyocytes and in adult murine hearts was sufficient to induce hypertrophy and HF. Conversely, MPC overexpression attenuated drug-induced hypertrophy in a cell-autonomous manner. We also introduced a novel, highly potent MCT4 inhibitor that mitigated hypertrophy in cultured cardiomyocytes and in mice. Together, we find that alteration of the pyruvate-lactate axis is a fundamental and early feature of cardiac hypertrophy and failure.

11.
Mol Metab ; 45: 101145, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33352310

RESUMO

OBJECTIVE: Aging and weight gain lead to a decline in brown and beige adipocyte functionality that exacerbates obesity and insulin resistance. We sought to determine whether sphingolipids, such as ceramides, a class of lipid metabolites that accumulate in aging and overnutrition, are sufficient or necessary for the metabolic impairment of these thermogenic adipocytes. METHODS: We generated new mouse models allowing for the conditional ablation of genes required for ceramide synthesis (i.e., serine palmitoyltransferase subunit 2, Sptlc2) or degradation (i.e., acid ceramidase 1, Asah1) from mature, thermogenic adipocytes (i.e., from cells expressing uncoupling protein-1). Mice underwent a comprehensive suite of phenotyping protocols to assess energy expenditure and glucose and lipid homeostasis. Complementary studies were conducted in primary brown adipocytes to dissect the mechanisms controlling ceramide synthesis or action. RESULTS: Depletion of Sptlc2 increased energy expenditure, improved glucose homeostasis, and prevented diet-induced obesity. Conversely, depletion of Asah1 led to ceramide accumulation, diminution of energy expenditure, and exacerbation of insulin resistance and obesity. Mechanistically, ceramides slowed lipolysis, inhibited glucose uptake, and decreased mitochondrial respiration. Moreover, ß-adrenergic receptor agonists, which activate thermogenesis in brown adipocytes, decreased transcription of enzymes required for ceramide synthesis. CONCLUSIONS: These studies support our hypothesis that ceramides are necessary and sufficient for the impairment in thermogenic adipocyte function that accompanies obesity. Moreover, they suggest that implementation of therapeutic strategies to block ceramide synthesis in thermogenic adipocytes may serve as a means of improving adipose health and combating obesity and cardiometabolic disease.

12.
J Lipid Res ; 61(10): 1328-1340, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32690594

RESUMO

Sphingolipids have become established participants in the pathogenesis of obesity and its associated maladies. Sphingosine kinase 1 (SPHK1), which generates S1P, has been shown to increase in liver and adipose of obese humans and mice and to regulate inflammation in hepatocytes and adipose tissue, insulin resistance, and systemic inflammation in mouse models of obesity. Previous studies by us and others have demonstrated that global sphingosine kinase 1 KO mice are protected from diet-induced obesity, insulin resistance, systemic inflammation, and NAFLD, suggesting that SPHK1 may mediate pathological outcomes of obesity. As adipose tissue dysfunction has gained recognition as a central instigator of obesity-induced metabolic disease, we hypothesized that SPHK1 intrinsic to adipocytes may contribute to HFD-induced metabolic pathology. To test this, we depleted Sphk1 from adipocytes in mice (SK1fatKO) and placed them on a HFD. In contrast to our initial hypothesis, SK1fatKO mice displayed greater weight gain on HFD and exacerbated impairment in glucose clearance. Pro-inflammatory cytokines and neutrophil content of adipose tissue were similar, as were levels of circulating leptin and adiponectin. However, SPHK1-null adipocytes were hypertrophied and had lower basal lipolytic activity. Interestingly, hepatocyte triacylglycerol accumulation and expression of pro-inflammatory cytokines and collagen 1a1 were exacerbated in SK1fatKO mice on a HFD, implicating a specific role for adipocyte SPHK1 in adipocyte function and inter-organ cross-talk that maintains overall metabolic homeostasis in obesity. Thus, SPHK1 serves a previously unidentified essential homeostatic role in adipocytes that protects from obesity-associated pathology. These findings may have implications for pharmacological targeting of the SPHK1/S1P signaling axis.

13.
J Lipid Res ; 61(7): 983-994, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32398264

RESUMO

Alcohol's impairment of both hepatic lipid metabolism and insulin resistance (IR) are key drivers of alcoholic steatosis, the initial stage of alcoholic liver disease (ALD). Pharmacologic reduction of lipotoxic ceramide prevents alcoholic steatosis and glucose intolerance in mice, but potential off-target effects limit its strategic utility. Here, we employed a hepatic-specific acid ceramidase (ASAH) overexpression model to reduce hepatic ceramides in a Lieber-DeCarli model of experimental alcoholic steatosis. We examined effects of alcohol on hepatic lipid metabolism, body composition, energy homeostasis, and insulin sensitivity as measured by hyperinsulinemic-euglycemic clamp. Our results demonstrate that hepatic ceramide reduction ameliorates the effects of alcohol on hepatic lipid droplet (LD) accumulation by promoting VLDL secretion and lipophagy, the latter of which involves ceramide cross-talk between the lysosomal and LD compartments. We additionally demonstrate that hepatic ceramide reduction prevents alcohol's inhibition of hepatic insulin signaling. These effects on the liver are associated with a reduction in oxidative stress markers and are relevant to humans, as we observe peri- LD ASAH expression in human ALD. Together, our results suggest a potential role for hepatic ceramide inhibition in preventing ALD.

14.
J Gerontol A Biol Sci Med Sci ; 75(9): 1663-1670, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32215553

RESUMO

Acute bed rest places older adults at risk for health complications by disrupting homeostasis in many organ systems, including the cardiovascular system. Circulating ceramides are emerging biomarkers predictive of cardiovascular and metabolic health and have recently been shown to be sensitive indices of cardiovascular (CV) risk. Therefore, the purpose of this study was to characterize the time course of changes in circulating ceramides in healthy younger and older adults after 5 days of bed rest and to determine whether short-term bed rest alters CV-related circulating ceramides. We hypothesized that circulating ceramides predictive of poor cardiometabolic outcomes would increase following 5 days of bed rest. Thirty-five healthy younger and older men and women (young: n = 13, old: n = 22) underwent 5 days of controlled bed rest. Fasting blood samples collected daily during the course of bed rest were used to measure circulating ceramides, lipoproteins, adiponectin, and fibroblast growth factor 21 (FGF21) levels. The primary findings were that circulating ceramides decreased while ceramide ratios and the cardiac event risk test 1 score were increased primarily in older adults, and these findings were independent of changes in circulating lipoprotein levels. Additionally, we found that changes in circulating adiponectin, FGF21 and the 6-minute walk test (6MW) inversely correlated with CV-related circulating ceramides after bed rest. The results of this study highlight the sensitivity of circulating ceramides to detect potential CV dysfunction that may occur with acute physical disuse in aging.


Assuntos
Repouso em Cama/efeitos adversos , Doenças Cardiovasculares/etiologia , Ceramidas/sangue , Adiponectina/sangue , Fatores Etários , Idoso , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Dieta , Feminino , Fatores de Crescimento de Fibroblastos/sangue , Humanos , Resistência à Insulina , Masculino , Fatores de Risco , Adulto Jovem
15.
Chem Sci ; 11(1): 195-200, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-32110371

RESUMO

Although insulin was first purified and used therapeutically almost a century ago, there is still a need to improve therapeutic efficacy and patient convenience. A key challenge is the requirement for refrigeration to avoid inactivation of insulin by aggregation/fibrillation. Here, in an effort to mitigate this problem, we introduced a 4th disulfide bond between a C-terminal extended insulin A chain and residues near the C-terminus of the B chain. Insulin activity was retained by an analog with an additional disulfide bond between residues A22 and B22, while other linkages tested resulted in much reduced potency. Furthermore, the A22-B22 analog maintains the native insulin tertiary structure as demonstrated by X-ray crystal structure determination. We further demonstrate that this four-disulfide analog has similar in vivo potency in mice compared to native insulin and demonstrates higher aggregation stability. In conclusion, we have discovered a novel four-disulfide insulin analog with high aggregation stability and potency.

17.
Diabetes ; 69(3): 313-330, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31882562

RESUMO

Obesity-associated type 2 diabetes mellitus (T2DM) entails insulin resistance and loss of ß-cell mass. Adipose tissue mitochondrial dysfunction is emerging as a key component in the etiology of T2DM. Identifying approaches to preserve mitochondrial function, adipose tissue integrity, and ß-cell mass during obesity is a major challenge. Mitochondrial ferritin (FtMT) is a mitochondrial matrix protein that chelates iron. We sought to determine whether perturbation of adipocyte mitochondria influences energy metabolism during obesity. We used an adipocyte-specific doxycycline-inducible mouse model of FtMT overexpression (FtMT-Adip mice). During a dietary challenge, FtMT-Adip mice are leaner but exhibit glucose intolerance, low adiponectin levels, increased reactive oxygen species damage, and elevated GDF15 and FGF21 levels, indicating metabolically dysfunctional fat. Paradoxically, despite harboring highly dysfunctional fat, transgenic mice display massive ß-cell hyperplasia, reflecting a beneficial mitochondria-induced fat-to-pancreas interorgan signaling axis. This identifies the unique and critical impact that adipocyte mitochondrial dysfunction has on increasing ß-cell mass during obesity-related insulin resistance.


Assuntos
Adipócitos/metabolismo , Ferritinas/genética , Intolerância à Glucose/metabolismo , Células Secretoras de Insulina/metabolismo , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Obesidade/metabolismo , Adiponectina/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Metabolismo Energético/genética , Ferritinas/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Técnica Clamp de Glucose , Fator 15 de Diferenciação de Crescimento/metabolismo , Hiperplasia , Resistência à Insulina/genética , Células Secretoras de Insulina/patologia , Camundongos , Camundongos Transgênicos , Proteínas Mitocondriais/metabolismo , Espécies Reativas de Oxigênio/metabolismo
18.
J Clin Invest ; 130(3): 1363-1376, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-31743112

RESUMO

BACKGROUNDCeramides are sphingolipids that play causative roles in diabetes and heart disease, with their serum levels measured clinically as biomarkers of cardiovascular disease (CVD).METHODSWe performed targeted lipidomics on serum samples from individuals with familial coronary artery disease (CAD) (n = 462) and population-based controls (n = 212) to explore the relationship between serum sphingolipids and CAD, using unbiased machine learning to identify sphingolipid species positively associated with CAD.RESULTSNearly every sphingolipid measured (n = 30 of 32) was significantly elevated in subjects with CAD compared with measurements in population controls. We generated a novel sphingolipid-inclusive CAD risk score, termed SIC, that demarcates patients with CAD independently and more effectively than conventional clinical CVD biomarkers including serum LDL cholesterol and triglycerides. This new metric comprises several minor lipids that likely serve as measures of flux through the ceramide biosynthesis pathway rather than the abundant deleterious ceramide species that are included in other ceramide-based scores.CONCLUSIONThis study validates serum ceramides as candidate biomarkers of CVD and suggests that comprehensive sphingolipid panels should be considered as measures of CVD.FUNDINGThe NIH (DK112826, DK108833, DK115824, DK116888, and DK116450); the Juvenile Diabetes Research Foundation (JDRF 3-SRA-2019-768-A-B); the American Diabetes Association; the American Heart Association; the Margolis Foundation; the National Cancer Institute, NIH (5R00CA218694-03); and the Huntsman Cancer Institute Cancer Center Support Grant (P30CA040214).


Assuntos
Ceramidas/sangue , Doença da Artéria Coronariana/sangue , Aprendizado de Máquina , Adulto , Idoso , Biomarcadores/sangue , Colesterol/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
19.
J Med Chem ; 62(24): 11437-11443, 2019 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-31804076

RESUMO

Insulin has been a life-saving drug for millions of people with diabetes. However, several challenges exist which limit therapeutic benefits and reduce patient convenience. One key challenge is the fibrillation propensity, which necessitates refrigeration for storage. To address this limitation, we chemically synthesized and evaluated a methylene thioacetal human insulin analogue (SCS-Ins). The synthesized SCS-Ins showed enhanced serum stability and aggregation resistance while retaining bioactivity compared with native insulin.


Assuntos
Dissulfetos/química , Desenho de Fármacos , Insulina/química , Fragmentos de Peptídeos/química , Compostos de Sulfidrila/química , Sequência de Aminoácidos , Animais , Dissulfetos/metabolismo , Estabilidade de Medicamentos , Feminino , Humanos , Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/metabolismo , Conformação Proteica
20.
Cell Rep ; 29(2): 270-282.e5, 2019 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-31597091

RESUMO

Accumulation of visceral (VIS) is a predictor of metabolic disorders and insulin resistance. This is due in part to the limited capacity of VIS fat to buffer lipids allowing them to deposit in insulin-sensitive tissues. Mechanisms underlying selective hypertrophic growth and tissue remodeling properties of VIS fat are not well understood. We identified subsets of adipose progenitors (APs) unique to VIS fat with differential Cd34 expression and adipogenic capacity. VIS low (Cd34 low) APs are adipogenic, whereas VIS high (Cd34 high) APs are not. Furthermore, VIS high APs inhibit adipogenic differentiation of SUB and VIS low APs in vitro through the secretion of soluble inhibitory factor(s). The number of VIS high APs increased with adipose tissue expansion, and their abundance in vivo caused hypertrophic growth, fibrosis, inflammation, and metabolic dysfunction. This study unveils the presence of APs unique to VIS fat involved in the paracrine regulation of adipogenesis and tissue remodeling.


Assuntos
Antígenos CD34/metabolismo , Gordura Intra-Abdominal/citologia , Comunicação Parácrina , Transdução de Sinais , Células-Tronco/metabolismo , Adipogenia/efeitos dos fármacos , Tecido Adiposo Branco/citologia , Animais , Proteína Morfogenética Óssea 4/farmacologia , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Resistência à Insulina , Gordura Intra-Abdominal/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Músculo Liso/efeitos dos fármacos , Músculo Liso/metabolismo , Comunicação Parácrina/efeitos dos fármacos , Fenótipo , Rosiglitazona/farmacologia , Transdução de Sinais/efeitos dos fármacos , Solubilidade , Células-Tronco/efeitos dos fármacos , Ganho de Peso/efeitos dos fármacos
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