White-to-brown transdifferentiation of omental adipocytes in patients affected by pheochromocytoma

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WAT to BAT transdifferentiation of omental fat in adult humans affected by pheochromocytomas

In small mammals and to some extent also in humans, White Adipose Tissue (WAT) and Brown Adipose Tissue (BAT) are contained together in discrete locations at subcutaneous or visceral level forming a multi-depots organ [1]. We have recently described paucilocular cells immunoreactive for uncoupling protein 1 (UCP1-ir) as morphological marker of WAT-BAT transformation in the adipose organ of cold-exposed mice (hyper-adrenergic stimulation) [2]. In this study, we examined biopsies of omental WAT depot, in 20 controls and in 12 patients affected by pheochromocytomas used as model of adrenergic stimulation in humans. Histological examination was performed by light microscopy, immunohistochemistry and Electron Microscopy. qPCR was carried out to asses relative expression of “brown” genes. Control tissues were all formed by unilocular UCP1-negative adipocytes. Half of the omental fat samples from pheochromocytomas showed UCP1-ir multilocular cells forming BAT-islands among WAT. Several UCP1-ir paucilocular cells were also detected. Higher density of TH-ir fibres and capillaries were found in the transformed tissues. Ultrastructural examination, highlighted poorly differentiated cells in pericapillary position with features similar to those identified in supraclavicular human BAT [3]. In light of the protective role exerted by BAT against the development of obesity and other metabolic diseases, WAT to BAT plasticity could be an important target for the development of therapeutic strategies in the treatment of obesity and type II diabetes in humans

Brown adipose tissue whitening leads to brown adipocyte death and adipose tissue inflammation

In mammals, white adipose tissue (WAT) stores and releases lipids, whereas brown adipose tissue (BAT) oxidizes lipids to fuel thermogenesis. In obese individuals, WAT undergoes profound changes; it expands, becomes dysfunctional, and develops a low-grade inflammatory state. Importantly, BAT content and activity decline in obese subjects, mainly as a result of the conversion of brown adipocytes to white-like unilocular cells. Here, we show that BAT “whitening” is induced by multiple factors, including high ambient temperature, leptin receptor deficiency, -adrenergic signaling impairment, and lipase deficiency, each of which is capable of inducing macrophage infiltration, brown adipocyte death, and crown-like structure (CLS) formation. Brown-to-white conversion and increased CLS formation were most marked in BAT from adipose triglyceride lipase (Atgl)-deficient mice, where, according to transmission electron microscopy, whitened brown adipocytes contained enlarged endoplasmic reticulum, cholesterol crystals, and some degenerating mitochondria, and were surrounded by an increased number of collagen fibrils. Gene expression analysis showed that BAT whitening in Atgl-deficient mice was associated to a strong inflammatory response and NLRP3 inflammasome activation. Altogether, the present findings suggest that converted enlarged brown adipocytes are highly prone to death, which, by promoting inflammation in whitened BAT, may contribute to the typical inflammatory state seen in obesity. Copyright © 2018 by the American Society for Biochemistry and Molecular Biology, Inc

Brown adipose tissue whitening leads to brown adipocyte death and adipose tissue inflammation

In mammals, white adipose tissue (WAT) stores and releases lipids, whereas brown adipose tissue (BAT) oxidizes lipids to fuel thermogenesis. In obese individuals, WAT undergoes profound changes; it expands, becomes dysfunctional, and develops a low-grade inflammatory state. Importantly, BAT content and activity decline in obese subjects, mainly as a result of the conversion of brown adipocytes to white-like unilocular cells. Here, we show that BAT "whitening" is induced by multiple factors, including high ambient temperature, leptin receptor deficiency, \u3b2-adrenergic signaling impairment, and lipase deficiency, each of which is capable of inducing macrophage infiltration, brown adipocyte death, and crown-like structure (CLS) formation. Brown-to-white conversion and increased CLS formation were most marked in BAT from adipose triglyceride lipase (Atgl)-deficient mice, where, according to transmission electron microscopy, whitened brown adipocytes contained enlarged endoplasmic reticulum, cholesterol crystals, and some degenerating mitochondria, and were surrounded by an increased number of collagen fibrils. Gene expression analysis showed that BAT whitening in Atgl-deficient mice was associated to a strong inflammatory response and NLRP3 inflammasome activation. Altogether, the present findings suggest that converted enlarged brown adipocytes are highly prone to death, which, by promoting inflammation in whitened BAT, may contribute to the typical inflammatory state seen in obesity

p53 regulates expression of uncoupling protein 1 through binding and repression of PPARγ coactivator-1α

The tumor suppressor p53 (TRP53 in mice) is known for its involvement in carcinogenesis, but work during recent years has underscored the importance of p53 in the regulation of whole body metabolism. A general notion is that p53 is necessary for efficient oxidative metabolism. The importance of UCP1-dependent uncoupled respiration and increased oxidation of glucose and fatty acids in brown or brown-like, termed BRITE or beige, adipocytes in relation to energy balance and homeostasis has recently been highlighted. UCP1-dependent uncoupled respiration in classic interscapular brown adipose tissue is central to cold-induced thermogenesis, whereas BRITE/beige adipocytes are of special importance in relation to diet-induced thermogenesis, where the importance of UCP1 is only clearly manifested in mice kept at thermoneutrality. We challenged wildtype and TRP53-deficient mice by high fat feeding under thermoneutral conditions. Interestingly, mice lacking TRP53 gained less weight compared to their wildtype counterparts. This was related to an increased expression of Ucp1 and other PPARGC1a and PPARGC1b target genes, but not Ppargc1a or Ppargc1b in inguinal white adipose tissue of mice lacking TRP53. We show that TRP53, independently of its ability to bind DNA, inhibits the activity of PPARGC1a and PPARGC1b. Collectively, our data shows that TRP53 has the ability to regulate the thermogenic capacity of adipocytes through modulation of PPARGC1 activity

Neuronal Protein Tyrosine Phosphatase 1B Deficiency Results in Inhibition of Hypothalamic AMPK and Isoform-Specific Activation of AMPK in Peripheral Tissues▿ †

PTP1B−/− mice are resistant to diet-induced obesity due to leptin hypersensitivity and consequent increased energy expenditure. We aimed to determine the cellular mechanisms underlying this metabolic state. AMPK is an important mediator of leptin's metabolic effects. We find that α1 and α2 AMPK activity are elevated and acetyl-coenzyme A carboxylase activity is decreased in the muscle and brown adipose tissue (BAT) of PTP1B−/− mice. The effects of PTP1B deficiency on α2, but not α1, AMPK activity in BAT and muscle are neuronally mediated, as they are present in neuron- but not muscle-specific PTP1B−/− mice. In addition, AMPK activity is decreased in the hypothalamic nuclei of neuronal and whole-body PTP1B−/− mice, accompanied by alterations in neuropeptide expression that are indicative of enhanced leptin sensitivity. Furthermore, AMPK target genes regulating mitochondrial biogenesis, fatty acid oxidation, and energy expenditure are induced with PTP1B inhibition, resulting in increased mitochondrial content in BAT and conversion to a more oxidative muscle fiber type. Thus, neuronal PTP1B inhibition results in decreased hypothalamic AMPK activity, isoform-specific AMPK activation in peripheral tissues, and downstream gene expression changes that promote leanness and increased energy expenditure. Therefore, the mechanism by which PTP1B regulates adiposity and leptin sensitivity likely involves the coordinated regulation of AMPK in hypothalamus and peripheral tissues