RESUMEN
OBJECTIVE: The susceptibility to abdominal obesity and the metabolic syndrome is determined to a substantial extent during childhood and adolescence, when key adipose tissue characteristics are established. Although the general impact of postnatal nutrition is well known, it is not clear how specific dietary components drive adipose tissue growth and how this relates to the risk of metabolic dysfunction in adulthood. METHODS: Adipose tissue growth including cell proliferation was analyzed in juvenile mice upon dietary manipulation with in vivo nucleotide labeling. The proliferative response of progenitors to specific fatty acids was assayed in primary cultures. Long-term metabolic consequences were assessed through transient dietary manipulation post-weaning with a second obesogenic challenge in adulthood. RESULTS: Dietary lipids stimulated adipose tissue progenitor cell proliferation in juvenile mice independently of excess caloric intake and calorie-dependent adipocyte hypertrophy. Excess calories increased mitogenic IGF-1 levels systemically, whereas palmitoleic acid was able to enhance the sensitivity of progenitors to IGF-1, resulting in synergistic stimulation of proliferation. Early transient consumption of excess lipids promoted hyperplastic adipose tissue expansion in response to a second dietary challenge in adulthood and this correlated with abdominal obesity and hyperinsulinemia. CONCLUSIONS: Dietary lipids and calories differentially and synergistically drive adipose tissue proliferative growth and the programming of the metabolic syndrome in childhood.
Asunto(s)
Grasa Abdominal/crecimiento & desarrollo , Grasas de la Dieta/metabolismo , Ingestión de Energía , Obesidad Infantil/etiología , Grasa Abdominal/metabolismo , Adipocitos/metabolismo , Adipocitos/fisiología , Animales , Proliferación Celular , Células Cultivadas , Femenino , Factor I del Crecimiento Similar a la Insulina/metabolismo , Metabolismo de los Lípidos , Ratones , Ratones Endogámicos C57BLRESUMEN
Most antidiabetic drugs treat disease symptoms rather than adipose tissue dysfunction as a key pathogenic cause in the metabolic syndrome and type 2 diabetes. Pharmacological targeting of adipose tissue through the nuclear receptor PPARg, as exemplified by glitazone treatments, mediates efficacious insulin sensitization. However, a better understanding of the context-specific PPARg responses is required for the development of novel approaches with reduced side effects. Here, we identified the transcriptional cofactor Cited4 as a target and mediator of rosiglitazone in human and murine adipocyte progenitor cells, where it promoted specific sets of the rosiglitazone-dependent transcriptional program. In mice, Cited4 was required for the proper induction of thermogenic expression by Rosi specifically in subcutaneous fat. This phenotype had high penetrance in females only and was not evident in beta-adrenergically stimulated browning. Intriguingly, this specific defect was associated with reduced capacity for systemic thermogenesis and compromised insulin sensitization upon therapeutic rosiglitazone treatment in female but not male mice. Our findings on Cited4 function reveal novel unexpected aspects of the pharmacological targeting of PPARg.
Asunto(s)
Adipocitos/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Rosiglitazona/uso terapéutico , Factores de Transcripción/metabolismo , Adipocitos/metabolismo , Animales , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Humanos , Masculino , Ratones , Terapia Molecular Dirigida , PPAR gamma/metabolismo , Factores Sexuales , Células Madre/efectos de los fármacos , Células Madre/metabolismo , Termogénesis , Factores de Transcripción/biosíntesis , Transcripción Genética/efectos de los fármacos , Proteína Desacopladora 1/biosíntesisRESUMEN
The transient activation of inflammatory networks is required for adipose tissue remodeling including the "browning" of white fat in response to stimuli such as ß3-adrenergic receptor activation. In this process, white adipose tissue acquires thermogenic characteristics through the recruitment of so-called beige adipocytes. We investigated the downstream signaling pathways impinging on adipocyte progenitors that promote de novo formation of adipocytes. We showed that the Jak family of kinases controlled TGFß signaling in the adipose tissue microenvironment through Stat3 and thereby adipogenic commitment, a function that was required for beige adipocyte differentiation of murine and human progenitors. Jak/Stat3 inhibited TGFß signaling to the transcription factors Srf and Smad3 by repressing local Tgfb3 and Tgfb1 expression before the core transcriptional adipogenic cascade was activated. This pathway cross-talk was triggered in stromal cells by ATGL-dependent adipocyte lipolysis and a transient wave of IL-6 family cytokines at the onset of adipose tissue remodeling induced by ß3-adrenergic receptor stimulation. Our results provide insight into the activation of adipocyte progenitors and are relevant for the therapeutic targeting of adipose tissue inflammatory pathways.
Asunto(s)
Adipocitos Beige/metabolismo , Tejido Adiposo/metabolismo , Inflamación/genética , Quinasas Janus/genética , Factor de Crecimiento Transformador beta/genética , Adipocitos Beige/patología , Adipogénesis/genética , Tejido Adiposo/patología , Animales , Diferenciación Celular/genética , Células Cultivadas , Femenino , Perfilación de la Expresión Génica , Humanos , Inflamación/metabolismo , Quinasas Janus/metabolismo , Lipasa/genética , Lipasa/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/genética , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Appropriate cell models are necessary for the investigation of thermogenic beige adipocyte differentiation from progenitor cells. Here, we describe a primary cell culture method that is based on defined progenitor cells from murine white adipose tissue and aims at minimizing confounding factors including cell heterogeneity and nonphysiological differentiation inducers. Adipocyte progenitor cells are enriched by immuno-magnetic separation, expanded minimally, and induced for beige adipocyte differentiation with carbaprostacyclin, a stable analogue of the endogenous mediator PGI2.