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HMGA1 overexpression in adipose tissue impairs adipogenesis and prevents diet-induced obesity and insulin resistance.

ABSTRACT: High-Mobility-Group-A1 (HMGA1) proteins are non-histone proteins that regulate chromatin structure and gene expression during embryogenesis, tumourigenesis and immune responses. In vitro studies suggest that HMGA1 proteins may be required to regulate adipogenesis. To examine the role of HMGA1 in vivo, we generated transgenic mice overexpressing HMGA1 in adipose tissues. HMGA1 transgenic mice showed a marked reduction in white and brown adipose tissue mass that was associated with downregulation of genes involved in adipogenesis and concomitant upregulation of preadipocyte markers. Reduced adipogenesis and decreased fat mass were not associated with altered glucose homeostasis since HMGA1 transgenic mice fed a regular-chow diet exhibited normal glucose tolerance and insulin sensitivity. However, when fed a high-fat diet, overexpression of HMGA1 resulted in decreased body-weight gain, reduced fat mass, but improved insulin sensitivity and glucose tolerance. Although HMGA1 transgenic mice exhibited impaired glucose uptake in adipose tissue due to impaired adipogenesis, the increased glucose uptake observed in skeletal muscle may account for the improved glucose homeostasis. Our results indicate that HMGA1 plays an important function in the regulation of white and brown adipogenesis in vivo and suggests that impaired adipocyte differentiation and decreased fat mass is not always associated with impaired whole-body glucose homeostasis.

SUBMITTER: Arce-Cerezo A

PROVIDER: S-EPMC4585969 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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HMGA1 overexpression in adipose tissue impairs adipogenesis and prevents diet-induced obesity and insulin resistance.

Arce-Cerezo Altamira A García Miquel M Rodríguez-Nuevo Aida A Crosa-Bonell Mireia M Enguix Natalia N Peró Albert A Muñoz Sergio S Roca Carles C Ramos David D Franckhauser Sylvie S Elias Ivet I Ferre Tura T Pujol Anna A Ruberte Jesús J Villena Josep A JA Bosch Fàtima F Riu Efrén E

Scientific reports 20150928

High-Mobility-Group-A1 (HMGA1) proteins are non-histone proteins that regulate chromatin structure and gene expression during embryogenesis, tumourigenesis and immune responses. In vitro studies suggest that HMGA1 proteins may be required to regulate adipogenesis. To examine the role of HMGA1 in vivo, we generated transgenic mice overexpressing HMGA1 in adipose tissues. HMGA1 transgenic mice showed a marked reduction in white and brown adipose tissue mass that was associated with downregulation ...[more]

PMID: 26411793

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Project description:Aims/hypothesisAbsent in melanoma 2 (AIM2) is a cytosolic sensor for double-stranded DNA and a tumour suppressor. Binding of double-stranded DNA to AIM2 forms the AIM2 inflammasome, leading to activation of caspase-1 and production of IL-1β and IL-18. Although inflammasome-independent effects of AIM2 have been reported, its role in energy metabolism is unknown. We aimed to evaluate the effect of AIM2 in energy metabolism and glucose homeostasis.MethodsMale and female whole body Aim2 knockout (Aim2-/-) mice were used in the current study. Body weight, food intake, body composition, energy expenditure, fasting blood glucose levels, GTT and body temperature were measured at indicated time points. RNA sequencing was carried out on gonadal white adipose tissue (gWAT) in 14-month-old female mice. mRNA and protein levels in tissues were analysed by quantitative real-time PCR and immunoblot. Immune cell infiltration in gWAT was examined by flow cytometry. Stromal vascular fractions isolated from gWAT were used to investigate adipocyte differentiation.ResultsMale and female Aim2-/- mice were obese compared with wild-type controls from 7 weeks of age until 51 weeks of age, with increased adiposity in both subcutaneous and visceral fat depots. While there were no differences in food intake, Aim2-/- mice demonstrated decreased energy expenditure and impaired brown adipose tissue function compared with wild-type controls. Fasting glucose and insulin levels were elevated, and Aim2-/- mice were glucose intolerant on intraperitoneal GTT. RNA sequencing revealed marked upregulation of the IFN-inducible gene Ifi202b, which encodes protein 202 (p202) and elevated inflammatory signalling in gWAT of Aim2-/- mice. Increased infiltration of total and Ly6Clow monocytes was noted at 8 weeks of age in gWAT, before the onset of obesity and insulin resistance. Ifi202b knockdown blocked adipogenesis in stromal vascular fractions and reduced inflammation in bone marrow-derived macrophages, demonstrating a key role of p202 in mediating the increased adipogenesis and inflammation in Aim2-/- mice.Conclusions/interpretationThese results demonstrate a fundamental role for AIM2 in energy metabolism, inflammation and insulin resistance. Our studies establish a novel link between the innate immunity proteins, AIM2 and p202, and metabolism.

Dataset Information

HMGA1 overexpression in adipose tissue impairs adipogenesis and prevents diet-induced obesity and insulin resistance.

Publications

HMGA1 overexpression in adipose tissue impairs adipogenesis and prevents diet-induced obesity and insulin resistance.

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