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1.
Nat Metab ; 2(5): 397-412, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32440655

RESUMO

Human thermogenic adipose tissue mitigates metabolic disease, raising much interest in understanding its development and function. Here, we show that human thermogenic adipocytes specifically express a primate-specific long non-coding RNA, LINC00473 which is highly correlated with UCP1 expression and decreased in obesity and type-2 diabetes. LINC00473 is detected in progenitor cells, and increases upon differentiation and in response to cAMP. In contrast to other known adipocyte LincRNAs, LINC00473 shuttles out of the nucleus, colocalizes and can be crosslinked to mitochondrial and lipid droplet proteins. Up- or down- regulation of LINC00473 results in reciprocal alterations in lipolysis, respiration and transcription of genes associated with mitochondrial oxidative metabolism. Depletion of PLIN1 results in impaired cAMP-responsive LINC00473 expression and lipolysis, indicating bidirectional interactions between PLIN1, LINC00473 and mitochondrial oxidative functions. Thus, we suggest that LINC00473 is a key regulator of human thermogenic adipocyte function, and reveals a role for a LincRNA in inter-organelle communication and human energy metabolism.


Assuntos
Adipócitos/fisiologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/fisiologia , Termogênese/genética , Termogênese/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Comunicação Celular/genética , Comunicação Celular/fisiologia , Núcleo Celular/metabolismo , Células Cultivadas , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Metabolismo Energético/genética , Metabolismo Energético/fisiologia , Ácidos Graxos não Esterificados/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Gotículas Lipídicas , Masculino , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/metabolismo , Consumo de Oxigênio/genética , Consumo de Oxigênio/fisiologia , Perilipina-1/deficiência , Perilipina-1/genética , Proteína Desacopladora 1/biossíntese , Proteína Desacopladora 1/genética , Adulto Jovem
2.
J Biol Chem ; 293(36): 13974-13988, 2018 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-30042231

RESUMO

Lipid droplets are specialized cellular organelles that contain neutral lipid metabolites and play dynamic roles in energy homeostasis. Perilipin 1 (Plin1), one of the major lipid droplet-binding proteins, is highly expressed in adipocytes. In mice, Plin1 deficiency impairs peripheral insulin sensitivity, accompanied with reduced fat mass. However, the mechanisms underlying insulin resistance in lean Plin1 knockout (Plin1-/-) mice are largely unknown. The current study demonstrates that Plin1 deficiency promotes inflammatory responses and lipolysis in adipose tissue, resulting in insulin resistance. M1-type adipose tissue macrophages (ATMs) were higher in Plin1-/- than in Plin1+/+ mice on normal chow diet. Moreover, using lipidomics analysis, we discovered that Plin1-/- adipocytes promoted secretion of pro-inflammatory lipid metabolites such as prostaglandins, which potentiated monocyte migration. In lean Plin1-/- mice, insulin resistance was relieved by macrophage depletion with clodronate, implying that elevated pro-inflammatory ATMs might be attributable for insulin resistance under Plin1 deficiency. Together, these data suggest that Plin1 is required to restrain fat loss and pro-inflammatory responses in adipose tissue by reducing futile lipolysis to maintain metabolic homeostasis.


Assuntos
Tecido Adiposo/patologia , Inflamação/etiologia , Metabolismo dos Lipídeos , Perilipina-1/deficiência , Adipócitos/metabolismo , Animais , Resistência à Insulina , Lipólise , Macrófagos/patologia , Camundongos , Camundongos Knockout
3.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1863(2): 212-218, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29191637

RESUMO

Fatty liver features triglyceride accumulation in hepatocytes and often occurs with obesity and lipodystrophy in humans. Here, we investigated the mechanism of maladaptive hepatosteatosis with adipose-tissue dysfunction. Perilipin 1 (Plin1) did not exist in hepatocytes but was expressed exclusively in adipocytes as a dual modulator for regulating two principal adipose-tissue functions, triglyceride storage and breakdown. Plin1-/- mice showed decreased fat storage but increased lipolysis and efflux of fatty acids from adipose tissue, and hepatosteatosis spontaneously developed without altered circulating inflammatory adipocytokine levels. Plin1-/- adipose dysfunction impaired insulin sensitivity and hepatic glucose metabolism, which might inhibit gluconeogenesis to produce more intermediates for hepatic lipid synthesis. Indeed, the livers of Plin1-/- mice exhibited upregulated mRNA and protein expression of key enzymes and transcriptional factors for the uptake and transport of fatty acids and for de novo synthesis of triglycerides, but the expression of key enzymes and transcriptional factors for fatty-acid oxidation was downregulated. Biochemical assays in Plin1-/- mice confirmed increased fatty acid synthase activity but decreased activity of mitochondrial carnitine palmitoyltransferase 1 and [3H]-palmitate oxidation in the liver. We concluded that dysregulation of two principal functions, adipose storage and hydrolysis, had deleterious consequences on the hepatic lipid metabolism and thereby caused maladaptive hepatosteatosis. This mouse model might mimic and explain the pathogenesis of hepatosteatosis occurring in two typical disorders of adipose tissue dysfunction, obesity and lipodystrophy, particularly in lipodystrophic patients with Plin1 mutation.


Assuntos
Tecido Adiposo , Fígado Gorduroso , Hepatócitos , Metabolismo dos Lipídeos , Fígado , Perilipina-1/deficiência , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Knockout
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