Altered adipose tissue and adipocyte function in the pathogenesis of metabolic syndrome

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Abstract

Over the past decade, great progress has been made in understanding the complexity of adipose tissue biology and its role in metabolism. This includes new insights into the multiple layers of adipose tissue heterogeneity, not only differences between white and brown adipocytes, but also differences in white adipose tissue at the depot level and even heterogeneity of white adipocytes within a single depot. These inter- and intra-depot differences in adipocytes are developmentally programmed and contribute to the wide range of effects observed in disorders with fat excess (overweight/obesity) or fat loss (lipodystrophy). Recent studies also highlight the underappreciated dynamic nature of adipose tissue, including potential to undergo rapid turnover and dedifferentiation and as a source of stem cells. Finally, we explore the rapidly expanding field of adipose tissue as an endocrine organ, and how adipose tissue communicates with other tissues to regulate systemic metabolism both centrally and peripherally through secretion of adipocyte-derived peptide hormones, inflammatory mediators, signaling lipids, and miRNAs packaged in exosomes. Together these attributes and complexities create a robust, multidimensional signaling network that is central to metabolic homeostasis.

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Abdominal visceral and subcutaneous adipose tissue compartments: association with metabolic risk factors in the Framingham Heart Study.

Caroline S. Fox, Joseph Massaro, Udo Hoffmann … (2007)

Visceral adipose tissue (VAT) compartments may confer increased metabolic risk. The incremental utility of measuring both visceral and subcutaneous abdominal adipose tissue (SAT) in association with metabolic risk factors and underlying heritability has not been well described in a population-based setting. Participants (n=3001) were drawn from the Framingham Heart Study (48% women; mean age, 50 years), were free of clinical cardiovascular disease, and underwent multidetector computed tomography assessment of SAT and VAT volumes between 2002 and 2005. Metabolic risk factors were examined in relation to increments of SAT and VAT after multivariable adjustment. Heritability was calculated using variance-components analysis. Among both women and men, SAT and VAT were significantly associated with blood pressure, fasting plasma glucose, triglycerides, and high-density lipoprotein cholesterol and with increased odds of hypertension, impaired fasting glucose, diabetes mellitus, and metabolic syndrome (P range < 0.01). In women, relations between VAT and risk factors were consistently stronger than in men. However, VAT was more strongly correlated with most metabolic risk factors than was SAT. For example, among women and men, both SAT and VAT were associated with increased odds of metabolic syndrome. In women, the odds ratio (OR) of metabolic syndrome per 1-standard deviation increase in VAT (OR, 4.7) was stronger than that for SAT (OR, 3.0; P for difference between SAT and VAT < 0.0001); similar differences were noted for men (OR for VAT, 4.2; OR for SAT, 2.5). Furthermore, VAT but not SAT contributed significantly to risk factor variation after adjustment for body mass index and waist circumference (P < or = 0.01). Among overweight and obese individuals, the prevalence of hypertension, impaired fasting glucose, and metabolic syndrome increased linearly and significantly across increasing VAT quartiles. Heritability values for SAT and VAT were 57% and 36%, respectively. Although both SAT and VAT are correlated with metabolic risk factors, VAT remains more strongly associated with an adverse metabolic risk profile even after accounting for standard anthropometric indexes. Our findings are consistent with the hypothesized role of visceral fat as a unique, pathogenic fat depot. Measurement of VAT may provide a more complete understanding of metabolic risk associated with variation in fat distribution.

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Jason Fish, Massimo M. Santoro, Sarah Morton … (2008)

Precise regulation of the formation, maintenance, and remodeling of the vasculature is required for normal development, tissue response to injury, and tumor progression. How specific microRNAs intersect with and modulate angiogenic signaling cascades is unknown. Here, we identified microRNAs that were enriched in endothelial cells derived from mouse embryonic stem (ES) cells and in developing mouse embryos. We found that miR-126 regulated the response of endothelial cells to VEGF. Additionally, knockdown of miR-126 in zebrafish resulted in loss of vascular integrity and hemorrhage during embryonic development. miR-126 functioned in part by directly repressing negative regulators of the VEGF pathway, including the Sprouty-related protein SPRED1 and phosphoinositol-3 kinase regulatory subunit 2 (PIK3R2/p85-beta). Increased expression of Spred1 or inhibition of VEGF signaling in zebrafish resulted in defects similar to miR-126 knockdown. These findings illustrate that a single miRNA can regulate vascular integrity and angiogenesis, providing a new target for modulating vascular formation and function.

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Identification and expression cloning of a leptin receptor, OB-R.

Louis A Tartaglia, Marlene Dembski, Xun Weng … (1995)

The ob gene product, leptin, is an important circulating signal for the regulation of body weight. To identify high affinity leptin-binding sites, we generated a series of leptin-alkaline phosphatase (AP) fusion proteins as well as [125I]leptin. After a binding survey of cell lines and tissues, we identified leptin-binding sites in the mouse choroid plexus. A cDNA expression library was prepared from mouse choroid plexus and screened with a leptin-AP fusion protein to identify a leptin receptor (OB-R). OB-R is a single membrane-spanning receptor most related to the gp130 signal-transducing component of the IL-6 receptor, the G-CSF receptor, and the LIF receptor. OB-R mRNA is expressed not only in choroid plexus, but also in several other tissues, including hypothalamus. Genetic mapping of the gene encoding OB-R shows that it is within the 5.1 cM interval of mouse chromosome 4 that contains the db locus.