Publications by authors named "Saverio Cinti"

149 Publications

Predictors of Worse Prognosis in Young and Middle-Aged Adults Hospitalized with COVID-19 Pneumonia: A Multi-Center Italian Study (COVID-UNDER50).

J Clin Med 2021 Mar 15;10(6). Epub 2021 Mar 15.

Center of Epidemiology, Biostatistics and Information Technology, Department of Biomedical Sciences and Public Health, Marche Polytechnic University, 60020 Ancona, Italy.

Obesity as well as metabolic and cardiovascular comorbidities are established, significant predictors of worse prognosis in the overall COVID-19 population, but limited information is available on their roles in young and middle-aged adults (aged ≤ 50 years). The main objectives of the present Italian multi-center study were to describe clinical characteristics and role of selected prognostic predictors in a large cohort of young and middle-aged hospitalized patients. Nine pulmonology units, across north and center of Italy, were involved in this retrospective study. Comorbidities were classified according to their known or potential association with COVID-19. A total of 263 subjects were included. The prevalence of obesity was 25.9%, mechanical ventilation (MV) was needed in 27.7%, and 28 in-hospital deaths occurred (10.6%). Obesity and older age were the only independent, significant predictors for MV. Comorbidities, such as hypertension, diabetes, asthma, and increased D-dimer levels were significantly associated with higher mortality risk, regardless of age, body mass index, and MV. Obesity in young and middle-aged adults is a strong predictor of a more complicated COVID-19, without, however, evidence of a significant effect on in-hospital mortality. Selected comorbidities, including hypertension, diabetes and asthma, significantly impact survival even in a younger population, suggesting the need for prompt recognition of these conditions.
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http://dx.doi.org/10.3390/jcm10061218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999047PMC
March 2021

Mammary gland adipocytes in lactation cycle, obesity and breast cancer.

Rev Endocr Metab Disord 2021 Mar 22. Epub 2021 Mar 22.

Department of Experimental and Clinical Medicine, Center of Obesity, Marche Polytechnic University, Via Tronto, 10A 60020, Ancona, Italy.

The mammary gland (MG) is an exocrine gland present in female mammals responsible for the production and secretion of milk during the process of lactation. It is mainly composed by epithelial cells and adipocytes. Among the features that make the MG unique there are 1) its highly plastic properties displayed during pregnancy, lactation and involution (all steps belonging to the lactation cycle) and 2) its requirement to grow in close association with adipocytes which are absolutely necessary to ensure MG's proper development at puberty and remodeling during the lactation cycle. Although MG adipocytes play such a critical role for the gland development, most of the studies have focused on its epithelial component only, leaving the role of the neighboring adipocytes largely unexplored. In this review we aim to describe evidences regarding MG's adipocytes role and properties in physiologic conditions (gland development and lactation cycle), obesity and breast cancer, emphasizing the existing gaps in the literature which deserve further investigation.
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http://dx.doi.org/10.1007/s11154-021-09633-5DOI Listing
March 2021

Epidermal Acyl-CoA-binding protein is indispensable for systemic energy homeostasis.

Mol Metab 2021 02 18;44:101144. Epub 2020 Dec 18.

Department of Biochemistry and Molecular Biology, Villum Center for Bioanalytical Sciences, University of Southern Denmark, Campusvej 55, 5230, Odense M, Denmark. Electronic address:

Objectives: The skin is the largest sensory organ of the human body and plays a fundamental role in regulating body temperature. However, adaptive alterations in skin functions and morphology have only vaguely been associated with physiological responses to cold stress or sensation of ambient temperatures. We previously found that loss of acyl-CoA-binding protein (ACBP) in keratinocytes upregulates lipolysis in white adipose tissue and alters hepatic lipid metabolism, suggesting a link between epidermal barrier functions and systemic energy metabolism.

Methods: To assess the physiological responses to loss of ACBP in keratinocytes in detail, we used full-body ACBP and skin-specific ACBP knockout mice to clarify how loss of ACBP affects 1) energy expenditure by indirect calorimetry, 2) response to high-fat feeding and a high oral glucose load, and 3) expression of brown-selective gene programs by quantitative PCR in inguinal WAT (iWAT). To further elucidate the role of the epidermal barrier in systemic energy metabolism, we included mice with defects in skin structural proteins (ma/ma Flg) in these studies.

Results: We show that the ACBP mice and skin-specific ACBP knockout mice exhibited increased energy expenditure, increased food intake, browning of the iWAT, and resistance to diet-induced obesity. The metabolic phenotype, including browning of the iWAT, was reversed by housing the mice at thermoneutrality (30 °C) or pharmacological β-adrenergic blocking. Interestingly, these findings were phenocopied in flaky tail mice (ma/ma Flg). Taken together, we demonstrate that a compromised epidermal barrier induces a β-adrenergic response that increases energy expenditure and browning of the white adipose tissue to maintain a normal body temperature.

Conclusions: Our findings show that the epidermal barrier plays a key role in maintaining systemic metabolic homeostasis. Thus, regulation of epidermal barrier functions warrants further attention to understand the regulation of systemic metabolism in further detail.
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http://dx.doi.org/10.1016/j.molmet.2020.101144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797911PMC
February 2021

Gastric ghrelin cells in obese patients are hyperactive.

Int J Obes (Lond) 2021 Jan 23;45(1):184-194. Epub 2020 Nov 23.

Mediterranean Foundation "G.B. Morgagni", Catania, Italy.

Background/objectives: Distribution and activity of ghrelin cells in the stomach of obese subjects are controversial.

Subjects/methods: We examined samples from stomachs removed by sleeve gastrectomy in 49 obese subjects (normoglycemic, hyperglycemic and diabetic) and quantified the density of ghrelin/chromogranin endocrine cells by immunohistochemistry. Data were compared with those from 13 lean subjects evaluated by gastroscopy. In 44 cases (11 controls and 33 obese patients) a gene expression analysis of ghrelin and its activating enzyme ghrelin O-acyl transferase (GOAT) was performed. In 21 cases (4 controls and 17 obese patients) the protein levels of unacylated and acylated-ghrelin were measured by ELISA tests. In 18 cases (4 controls and 14 obese patients) the morphology of ghrelin-producing cells was evaluated by electron microscopy.

Results: The obese group, either considered as total population or divided into subgroups, did not show any significant difference in ghrelin cell density when compared with control subjects. Inter-glandular smooth muscle fibres were increased in obese patients. In line with a positive trend of the desacylated form found by ELISA, Ghrelin and GOAT mRNA expression in obese patients was significantly increased. The unique ghrelin cell ultrastructure was maintained in all obese groups. In the hyperglycemic obese patients, the higher ghrelin expression matched with ultrastructural signs of endocrine hyperactivity, including expanded rough endoplasmic reticulum and reduced density, size and electron-density of endocrine granules. A positive correlation between ghrelin gene expression and glycemic values, body mass index and GOAT was also found. All obese patients with type 2 diabetes recovered from diabetes at follow-up after 5 months with a 16.5% of weight loss.

Conclusions: Given the known inhibitory role on insulin secretion of ghrelin, these results suggest a possible role for gastric ghrelin overproduction in the complex architecture that takes part in the pathogenesis of type 2 diabetes.
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http://dx.doi.org/10.1038/s41366-020-00711-3DOI Listing
January 2021

Galectin-3 gene deletion results in defective adipose tissue maturation and impaired insulin sensitivity and glucose homeostasis.

Sci Rep 2020 11 18;10(1):20070. Epub 2020 Nov 18.

Department of Clinical and Molecular Medicine, "La Sapienza" University, Via di Grottarossa, 1035-1039, 00189, Rome, Italy.

Adiposopathy is a pathological adipose tissue (AT) response to overfeeding characterized by reduced AT expandability due to impaired adipogenesis, which favors inflammation, insulin resistance (IR), and abnormal glucose regulation. However, it is unclear whether defective adipogenesis causes metabolic derangement also independently of an increased demand for fat storage. As galectin-3 has been implicated in both adipocyte differentiation and glucose homeostasis, we tested this hypothesis in galectin-3 knockout (Lgal3) mice fed a standard chow. In vitro, Lgal3 adipocyte precursors showed impaired terminal differentiation (maturation). Two-month-old Lgal3 mice showed impaired AT maturation, with reduced adipocyte size and expression of adipogenic genes, but unchanged fat mass and no sign of adipocyte degeneration/death or ectopic fat accumulation. AT immaturity was associated with AT and whole-body inflammation and IR, glucose intolerance, and hyperglycemia. Five-month-old Lgal3 mice exhibited a more mature AT phenotype, with no difference in insulin sensitivity and expression of inflammatory cytokines versus WT animals, though abnormal glucose homeostasis persisted and was associated with reduced β-cell function. These data show that adipogenesis capacity per se affects AT function, insulin sensitivity, and glucose homeostasis independently of increased fat intake, accumulation and redistribution, thus uncovering a direct link between defective adipogenesis, IR and susceptibility to diabetes.
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http://dx.doi.org/10.1038/s41598-020-76952-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675972PMC
November 2020

snRNA-seq reveals a subpopulation of adipocytes that regulates thermogenesis.

Nature 2020 11 28;587(7832):98-102. Epub 2020 Oct 28.

Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland.

Adipose tissue is usually classified on the basis of its function as white, brown or beige (brite). It is an important regulator of systemic metabolism, as shown by the fact that dysfunctional adipose tissue in obesity leads to a variety of secondary metabolic complications. In addition, adipose tissue functions as a signalling hub that regulates systemic metabolism through paracrine and endocrine signals. Here we use single-nucleus RNA-sequencing (snRNA-seq) analysis in mice and humans to characterize adipocyte heterogeneity. We identify a rare subpopulation of adipocytes in mice that increases in abundance at higher temperatures, and we show that this subpopulation regulates the activity of neighbouring adipocytes through acetate-mediated modulation of their thermogenic capacity. Human adipose tissue contains higher numbers of cells of this subpopulation, which could explain the lower thermogenic activity of human compared to mouse adipose tissue and suggests that targeting this pathway could be used to restore thermogenic activity.
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http://dx.doi.org/10.1038/s41586-020-2856-xDOI Listing
November 2020

Manipulation of Dietary Amino Acids Prevents and Reverses Obesity in Mice Through Multiple Mechanisms That Modulate Energy Homeostasis.

Diabetes 2020 11 10;69(11):2324-2339. Epub 2020 Aug 10.

Center for Study and Research on Obesity, Department of Biomedical Technology and Translational Medicine, University of Milan, Milan, Italy

Reduced activation of energy metabolism increases adiposity in humans and other mammals. Thus, exploring dietary and molecular mechanisms able to improve energy metabolism is of paramount medical importance because such mechanisms can be leveraged as a therapy for obesity and related disorders. Here, we show that a designer protein-deprived diet enriched in free essential amino acids can ) promote the brown fat thermogenic program and fatty acid oxidation, ) stimulate uncoupling protein 1 (UCP1)-independent respiration in subcutaneous white fat, ) change the gut microbiota composition, and ) prevent and reverse obesity and dysregulated glucose homeostasis in multiple mouse models, prolonging the healthy life span. These effects are independent of unbalanced amino acid ratio, energy consumption, and intestinal calorie absorption. A brown fat-specific activation of the mechanistic target of rapamycin complex 1 seems involved in the diet-induced beneficial effects, as also strengthened by in vitro experiments. Hence, our results suggest that brown and white fat may be targets of specific amino acids to control UCP1-dependent and -independent thermogenesis, thereby contributing to the improvement of metabolic health.
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http://dx.doi.org/10.2337/db20-0489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576563PMC
November 2020

Biomarkers of Browning in Cold Exposed Siberian Adults.

Nutrients 2020 Jul 22;12(8). Epub 2020 Jul 22.

Center for the Study of Obesity, Department of Experimental and Clinical Medicine, Marche Polytechnic University, Via Tronto 10A, 60020 Ancona, Italy.

Cold-exposure promotes energy expenditure by inducing brown adipose tissue (BAT) thermogenesis, which over time, is also sustained by browning, the appearance, or increase, of brown-like cells into white fat depots. Identification of circulating markers reflecting BAT activity and browning is crucial to study this phenomenon and its triggers, also holding possible implications for the therapy of obesity and metabolic diseases. Using RT-qPCR, we evaluated the peripheral blood mononuclear cells (PBMC) expression profile of regulators of BAT activity (, ), white adipocytes browning ( and ), and fatty acid β-oxidation () in 150 Siberian healthy miners living at extremely cold temperatures compared to 29 healthy subjects living in thermoneutral conditions. Anthropometric parameters, glucose, and lipid profiles were also assessed. The cold-exposed group showed significantly lower weight, BMI, hip circumference, and PBMC expression of , but higher expression of and higher circulating glucose compared to controls. Within the cold-exposed group, BMI, total cholesterol, and the atherogenic coefficient were lower in individuals exposed to low temperatures for a longer time. In conclusion, human PBMC expresses the brown adipocytes marker and the browning marker , which, varying according to cold-exposure, possibly reflect changes in BAT activation and white fat browning.
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http://dx.doi.org/10.3390/nu12082162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468804PMC
July 2020

Human brown adipose tissue is phenocopied by classical brown adipose tissue in physiologically humanized mice.

Nat Metab 2019 08 19;1(8):830-843. Epub 2019 Aug 19.

Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.

Human and rodent brown adipose tissues (BAT) appear morphologically and molecularly different. Here we compare human BAT with both classical brown and brite/beige adipose tissues of 'physiologically humanized' mice: middle-aged mice living under conditions approaching human thermal and nutritional conditions, that is, prolonged exposure to thermoneutral temperature (approximately 30 °C) and to an energy-rich (high-fat, high-sugar) diet. We find that the morphological, cellular and molecular characteristics (both marker and adipose-selective gene expression) of classical brown fat, but not of brite/beige fat, of these physiologically humanized mice are notably similar to human BAT. We also demonstrate, both in silico and experimentally, that in physiologically humanized mice only classical BAT possesses a high thermogenic potential. These observations suggest that classical rodent BAT is the tissue of choice for translational studies aimed at recruiting human BAT to counteract the development of obesity and its comorbidities.
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http://dx.doi.org/10.1038/s42255-019-0101-4DOI Listing
August 2019

COVID-19 and Hartnup disease: an affair of intestinal amino acid malabsorption.

Eat Weight Disord 2020 Jul 20. Epub 2020 Jul 20.

Department of Molecular and Translational Medicine, University of Brescia, Brescia, 25123, Italy.

Since the outbreak of COVID-19, clinicians have tried every effort to fight the disease, and multiple drugs have been proposed. However, no proven effective therapies currently exist, and different clinical phenotypes complicate the situation. In clinical practice, many severe or critically ill COVID-19 patients developed gastrointestinal (GI) disturbances, including vomiting, diarrhoea, or abdominal pain, even in the absence of cough and dyspnea. Understanding the mechanism of GI disturbances is warranted for exploring better clinical care for COVID-19 patients. With evidence collected from clinical studies on COVID-19 and basic research on a rare genetic disease (i.e., Hartnup disorder), we put forward a novel hypothesis to elaborate an effective nutritional therapy. We hypothesize that SARS-CoV-2 spike protein, binding to intestinal angiotensin-converting enzyme 2, negatively regulates the absorption of neutral amino acids, and this could explain not only the GI, but also systemic disturbances in COVID-19. Amino acid supplements could be recommended.Level of evidence No level of evidence: Hypothesis article.
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http://dx.doi.org/10.1007/s40519-020-00963-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369504PMC
July 2020

Bone marrow adipose tissue is a unique adipose subtype with distinct roles in glucose homeostasis.

Nat Commun 2020 06 18;11(1):3097. Epub 2020 Jun 18.

University/BHF Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh BioQuarter, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK.

Bone marrow adipose tissue (BMAT) comprises >10% of total adipose mass, yet unlike white or brown adipose tissues (WAT or BAT) its metabolic functions remain unclear. Herein, we address this critical gap in knowledge. Our transcriptomic analyses revealed that BMAT is distinct from WAT and BAT, with altered glucose metabolism and decreased insulin responsiveness. We therefore tested these functions in mice and humans using positron emission tomography-computed tomography (PET/CT) with F-fluorodeoxyglucose. This revealed that BMAT resists insulin- and cold-stimulated glucose uptake, while further in vivo studies showed that, compared to WAT, BMAT resists insulin-stimulated Akt phosphorylation. Thus, BMAT is functionally distinct from WAT and BAT. However, in humans basal glucose uptake in BMAT is greater than in axial bones or subcutaneous WAT and can be greater than that in skeletal muscle, underscoring the potential of BMAT to influence systemic glucose homeostasis. These PET/CT studies characterise BMAT function in vivo, establish new methods for BMAT analysis, and identify BMAT as a distinct, major adipose tissue subtype.
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http://dx.doi.org/10.1038/s41467-020-16878-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303125PMC
June 2020

Ciliary Neurotrophic Factor Acts on Distinctive Hypothalamic Arcuate Neurons and Promotes Leptin Entry Into and Action on the Mouse Hypothalamus.

Front Cell Neurosci 2020 21;14:140. Epub 2020 May 21.

Section of Neuroscience and Cell Biology, Department of Experimental and Clinical Medicine, Università Politecnica Delle Marche, Ancona, Italy.

In humans and experimental animals, the administration of ciliary neurotrophic factor (CNTF) reduces food intake and body weight. To gain further insights into the mechanism(s) underlying its satiety effect, we: (i) evaluated the CNTF-dependent activation of the Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) pathway in mouse models where neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) neurons can be identified by green fluorescent protein (GFP); and (ii) assessed whether CNTF promotes leptin signaling in hypothalamic feeding centers. Immunohistochemical experiments enabled us to establish that intraperitoneal injection of mouse recombinant CNTF activated the JAK2-STAT3 pathway in a substantial proportion of arcuate nucleus (ARC) NPY neurons (18.68% ± 0.60 in 24-h fasted mice and 25.50% ± 1.17 in fed mice) but exerted a limited effect on POMC neurons (4.15% ± 0.33 in 24-h fasted mice and 2.84% ± 0.45 in fed mice). CNTF-responsive NPY neurons resided in the ventromedial ARC, facing the median eminence (ME), and were surrounded by albumin immunoreactivity, suggesting that they are located outside the blood-brain barrier (BBB). In both normally fed and high-fat diet (HFD) obese animals, CNTF activated extracellular signal-regulated kinase signaling in ME β1- and β2-tanycytes, an effect that has been linked to the promotion of leptin entry into the brain. Accordingly, compared to the animals treated with leptin, mice treated with leptin/CNTF showed: (i) a significantly greater leptin content in hypothalamic protein extracts; (ii) a significant increase in phospho-STAT3 (P-STAT3)-positive neurons in the ARC and the ventromedial hypothalamic nucleus of normally fed mice; and (iii) a significantly increased number of P-STAT3-positive neurons in the ARC and dorsomedial hypothalamic nucleus of HFD obese mice. Collectively, these data suggest that exogenously administered CNTF reduces food intake by exerting a leptin-like action on distinctive NPY ARC neurons and by promoting leptin signaling in hypothalamic feeding centers.
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http://dx.doi.org/10.3389/fncel.2020.00140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253709PMC
May 2020

COVID-19 and fat embolism: a hypothesis to explain the severe clinical outcome in people with obesity.

Int J Obes (Lond) 2020 08 8;44(8):1800-1802. Epub 2020 Jun 8.

Department of Biomedical Technology and Translational Medicine, Center for the Study and Research on Obesity, University of Milan, 20129, Milan, Italy.

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http://dx.doi.org/10.1038/s41366-020-0624-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279432PMC
August 2020

Cytoplasmic ciliary inclusions can reflect an abnormal ciliogenesis in respiratory epithelium.

Pediatr Pulmonol 2020 08 26;55(8):1874-1875. Epub 2020 May 26.

Department of Experimental and Clinical Medicine, Biology of Obesity-Electron Microscopy Unit, Center of Obesity, United Hospitals-Marche Polytechnic University, Ancona, Italy.

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http://dx.doi.org/10.1002/ppul.24859DOI Listing
August 2020

Optogenetic-induced sympathetic neuromodulation of brown adipose tissue thermogenesis.

FASEB J 2020 02 23;34(2):2765-2773. Epub 2019 Dec 23.

Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, Minnesota.

The brown adipose tissue (BAT) is a thermogenic organ that plays a major role in energy balance, obesity, and diabetes due to the potent glucose and lipid clearance that fuels its thermogenesis, which is largely mediated via sympathetic nervous system activation. However, thus far there has been little experimental validation of the hypothesis that selective neuromodulation of the sympathetic nerves innervating the BAT is sufficient to elicit thermogenesis in mice. We generated mice expressing blue light-activated channelrhodopsin-2 (ChR2) in the sympathetic nerves innervating the BAT using two different strategies: injecting the BAT of C57Bl/6J mice with AAV6-hSyn-ChR2 (H134R)-EYFP; crossbreeding tyrosine hydroxylase-Cre mice with floxed-stop ChR2-EYFP mice. The nerves in the BAT expressing ChR2 were selectively stimulated with a blue LED light positioned underneath the fat pad of anesthetized mice, while the BAT and core temperatures were simultaneously recorded. Using immunohistochemistry we confirmed the selective expression of EYFP in TH positive nerves fibers. In addition, local optogenetic stimulation of the sympathetic nerves induced significant increase in the BAT temperature followed by an increase in core temperature in mice expressing ChR2, but not in the respective controls. The BAT activation was also paralleled by increased levels of pre-UCP1 transcript. Our results demonstrate that local optogenetic stimulation of the sympathetic nerves is sufficient to elicit BAT and core thermogenesis, thus suggesting that peripheral neuromodulation has the potential to be exploited as an alternative to pharmacotherapies to elicit organ activation and thus ameliorate type 2 diabetes and/or obesity.
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http://dx.doi.org/10.1096/fj.201901361RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306786PMC
February 2020

A large proportion of mediastinal and perirenal visceral fat of Siberian adult people is formed by UCP1 immunoreactive multilocular and paucilocular adipocytes.

J Physiol Biochem 2020 May 18;76(2):185-192. Epub 2019 Dec 18.

Department Experimental and Clinical Medicine, Center of Obesity, School of Medicine, University of Ancona (Politecnica delle Marche), Via Tronto 10a, 60020, Ancona, Italy.

Many deleterious consequences for health of excessive fat accumulation are due to visceral fat. Browning of visceral fat is mainly cold dependent and has been proposed as a possible tool for future therapies of obesity and related disorders. In this paper, we studied the composition of mediastinal and perirenal visceral fat, collected at necropsy, of human adults that lived in Siberia, one of the coldest regions of the earth. Data showed that a consistent part of the mediastinal and perirenal fat (up to about 40%) had the morphology typical of brown adipocytes and that a relevant percentage of them (up to about 30%) also expressed the functional marker uncoupling protein 1 (UCP1). Patients living mainly outdoor had higher percentage of brown-like adipocytes with more intensely UCP1 immunoreactive cells. The presence of numerous UCP1 immunoreactive paucilocular cells, a transitional stage of transdifferentiating adipocytes, supports the idea that visceral fat can be converted to brown adipose tissue in adult humans in physiological conditions. Tyrosine hydroxylase immunoreactive noradrenergic parenchymal nerve fibers were positively correlated to the number of multilocular adipocytes in mediastinal fat, and a similar trend was also observed in the perirenal fat.
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http://dx.doi.org/10.1007/s13105-019-00721-4DOI Listing
May 2020

Biological Effects of Ciliary Neurotrophic Factor on hMADS Adipocytes.

Front Endocrinol (Lausanne) 2019 12;10:768. Epub 2019 Nov 12.

Department of Experimental and Clinical Medicine, Marche Polytechnic University, Ancona, Italy.

Administration of ciliary neurotrophic factor (CNTF) to experimental animals exerts anti-obesity effects by acting on multiple targets. In white adipose tissue CNTF reduces lipid content, promotes fatty acid (FA) oxidation and improves insulin sensitivity. This study was performed to establish whether CNTF exerts similar effects on human white adipocytes. To this end, adipose differentiation was induced in human multipotent adipose-derived stem (hMADS) cells. CNTF receptor α (CNTFRα) expression was assessed in hMADS cells and adipocytes by qRT-PCR, Western blotting, and immunocytochemistry. After administration of human recombinant CNTF, signaling pathways and gene expression were evaluated by Western blotting and qRT-PCR. Glucose uptake was assessed by measuring 2-nitrobenzodeoxyglucose uptake with a fluorescence plate reader. Lastly, CNTF-induced anti-inflammatory responses were evaluated in hMADS adipocytes stressed with tumor necrosis factor α (TNFα) for 24 h. Results showed that CNTFRα protein expression was higher in undifferentiated hMADS cells than in hMADS adipocytes, where it was however clearly detectable. In hMADS adipocytes, 1 nM CNTF strongly activated the JAK-STAT3 (Janus kinase-signaling transducer and activator of transcription 3) pathway and acutely and transiently activated the AMPK (AMP-activated protein kinase) and AKT (protein kinase B) pathways. Acute CNTF treatment for 20 min significantly increased basal glucose uptake and was associated with increased AKT phosphorylation. Longer-term (24 and 48 h) treatment reduced the expression of lipogenic markers (FA synthase and sterol regulatory element-binding protein-1) and increased the expression of lipolytic [hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL)] and mitochondrial (peroxisome proliferator-activated receptor γ coactivator-1α and carnitine palmitoyltransferase 1) markers. In TNFα-treated hMADS adipocytes, CNTF significantly reduced the expression of monocyte chemoattractant protein 1 and TNFα-induced AKT inhibition. Collectively, these findings demonstrate for the first time that CNTF plays a role also in human adipocytes, driving their metabolism toward a less lipid-storing and more energy-consuming phenotype.
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http://dx.doi.org/10.3389/fendo.2019.00768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861295PMC
November 2019

Melatonin Supplementation Decreases Hypertrophic Obesity and Inflammation Induced by High-Fat Diet in Mice.

Front Endocrinol (Lausanne) 2019 5;10:750. Epub 2019 Nov 5.

Post-graduate Program in Chemical Biology, Institute of Environmental Sciences, Chemical and Pharmaceutical, Universidade Federal de São Paulo-UNIFESP, Diadema, Brazil.

Obesity results from critical periods of positive energy balance characterized by caloric intake greater than energy expenditure. This disbalance promotes adipose tissue dysfunction which is related to other comorbidities. Melatonin is a low-cost therapeutic agent and studies indicate that its use may improve obesity-related disorders. To evaluate if the melatonin is efficient in delaying or even blocking the damages caused by excessive ingestion of a high-fat diet (HFD) in mice, as well as improving the inflammatory profile triggered by obesity herein, male C57BL/6 mice of 8 weeks were induced to obesity by a HFD and treated for 10 weeks with melatonin. The results demonstrate that melatonin supplementation attenuated serum triglyceride levels and total and LDL cholesterol and prevented body mass gain through a decreased lipogenesis rate and increased lipolytic capacity in white adipocytes, with a concomitant increment in oxygen consumption and and expression. Altogether, these effects prevented adipocyte hypertrophy caused by HFD and reflected in decreased adiposity. Finally, melatonin supplementation reduced the crown-like-structure (CLS) formation, characteristic of the inflammatory process by macrophage infiltration into white adipose tissue of obese subjects, as well as decreased the gene expression of inflammation-related factors, such as leptin and MCP1. Thus, the melatonin can be considered a potential therapeutic agent to attenuate the metabolic and inflammatory disorders triggered by obesity.
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http://dx.doi.org/10.3389/fendo.2019.00750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848267PMC
November 2019

Altered adipocyte differentiation and unbalanced autophagy in type 2 Familial Partial Lipodystrophy: an in vitro and in vivo study of adipose tissue browning.

Exp Mol Med 2019 08 2;51(8):1-17. Epub 2019 Aug 2.

CNR - National Research Council of Italy, Institute of Molecular Genetics "Luigi Luca Cavalli-Sforza", Unit of Bologna, Bologna, Italy.

Type-2 Familial Partial Lipodystrophy is caused by LMNA mutations. Patients gradually lose subcutaneous fat from the limbs, while they accumulate adipose tissue in the face and neck. Several studies have demonstrated that autophagy is involved in the regulation of adipocyte differentiation and the maintenance of the balance between white and brown adipose tissue. We identified deregulation of autophagy in laminopathic preadipocytes before induction of differentiation. Moreover, in differentiating white adipocyte precursors, we observed impairment of large lipid droplet formation, altered regulation of adipose tissue genes, and expression of the brown adipose tissue marker UCP1. Conversely, in lipodystrophic brown adipocyte precursors induced to differentiate, we noticed activation of autophagy, formation of enlarged lipid droplets typical of white adipocytes, and dysregulation of brown adipose tissue genes. In agreement with these in vitro results indicating conversion of FPLD2 brown preadipocytes toward the white lineage, adipose tissue from FPLD2 patient neck, an area of brown adipogenesis, showed a white phenotype reminiscent of its brown origin. Moreover, in vivo morpho-functional evaluation of fat depots in the neck area of three FPLD2 patients by PET/CT analysis with cold stimulation showed the absence of brown adipose tissue activity. These findings highlight a new pathogenetic mechanism leading to improper fat distribution in lamin A-linked lipodystrophies and show that both impaired white adipocyte turnover and failure of adipose tissue browning contribute to disease.
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http://dx.doi.org/10.1038/s12276-019-0289-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802660PMC
August 2019

Overexpression of cyclooxygenase-2 in adipocytes reduces fat accumulation in inguinal white adipose tissue and hepatic steatosis in high-fat fed mice.

Sci Rep 2019 06 20;9(1):8979. Epub 2019 Jun 20.

Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, Universitetsparken 13, DK-2100, Copenhagen, Denmark.

Cyclooxygenases are known as important regulators of metabolism and immune processes via conversion of C20 fatty acids into various regulatory lipid mediators, and cyclooxygenase activity has been implicated in browning of white adipose tissues. We generated transgenic (TG) C57BL/6 mice expressing the Ptgs2 gene encoding cyclooxygenase-2 (COX-2) in mature adipocytes. TG mice fed a high-fat diet displayed marginally lower weight gain with less hepatic steatosis and a slight improvement in insulin sensitivity, but no difference in glucose tolerance. Compared to littermate wildtype mice, TG mice selectively reduced inguinal white adipose tissue (iWAT) mass and fat cell size, whereas the epididymal (eWAT) fat depot remained unchanged. The changes in iWAT were accompanied by increased levels of specific COX-derived lipid mediators and increased mRNA levels of interleukin-33, interleukin-4 and arginase-1, but not increased expression of uncoupling protein 1 or increased energy expenditure. Epididymal WAT (eWAT) in TG mice exhibited few changes except from increased infiltration with eosinophils. Our findings suggest a role for COX-2-derived lipid mediators from adipocytes in mediating type 2 immunity cues in subcutaneous WAT associated with decreased hepatic steatosis, but with no accompanying induction of browning and increased energy expenditure.
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http://dx.doi.org/10.1038/s41598-019-45062-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586826PMC
June 2019

Anatomy and physiology of the nutritional system.

Authors:
Saverio Cinti

Mol Aspects Med 2019 08 10;68:101-107. Epub 2019 Apr 10.

University of Ancona (Politecnica delle Marche), Center of Obesity, Via Tronto 10a, 60020, Ancona, Italy; Policlinico Morgagni, Via Del Bosco 105, 95125 Catania, Italy. Electronic address:

The organisms of mammals are composed of organs cooperating as systems that are organized to perform functions which allow the survival of the individual and maintenance of the species. Thus, to reach the main goals of these functions we need systems that ensure nutrient uptake and distribution, thermogenesis, oxygen uptake and distribution, the discharge of toxic internal by-products, the defense from internal and external pathogens, gamete fertilization, and the fine-tuning of the activity of all the tissues composing the organs. Most of these activities also require interactions with the internal and external environment. The latter function is served by the nervous system and the others by the cardiovascular, respiratory, excretory, immune, reproductive and endocrine systems. Nutrient intake and distribution and thermoregulation are realized by the collaborative work of the adipose and the digestive organs. In this review I will outline data on adipose tissue anatomy and function which have been collected during the past 40 years. They provide a convergent body of evidence toward a new concept regarding the collaborative work between the adipose organ and the organs of the gastrointestinal tract, which constitute a system ensuring nutrient search, intake and distribution to the organism. Furthermore, the same system also seems to enable nutrient distribution to the offspring to ensure not only short-term but also long-term homeostasis.
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http://dx.doi.org/10.1016/j.mam.2019.04.001DOI Listing
August 2019

Adipocyte-secreted BMP8b mediates adrenergic-induced remodeling of the neuro-vascular network in adipose tissue.

Nat Commun 2018 11 26;9(1):4974. Epub 2018 Nov 26.

Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, CB2 0QQ, UK.

Activation of brown adipose tissue-mediated thermogenesis is a strategy for tackling obesity and promoting metabolic health. BMP8b is secreted by brown/beige adipocytes and enhances energy dissipation. Here we show that adipocyte-secreted BMP8b contributes to adrenergic-induced remodeling of the neuro-vascular network in adipose tissue (AT). Overexpression of bmp8b in AT enhances browning of the subcutaneous depot and maximal thermogenic capacity. Moreover, BMP8b-induced browning, increased sympathetic innervation and vascularization of AT were maintained at 28 °C, a condition of low adrenergic output. This reinforces the local trophic effect of BMP8b. Innervation and vascular remodeling effects required BMP8b signaling through the adipocytes to 1) secrete neuregulin-4 (NRG4), which promotes sympathetic axon growth and branching in vitro, and 2) induce a pro-angiogenic transcriptional and secretory profile that promotes vascular sprouting. Thus, BMP8b and NRG4 can be considered as interconnected regulators of neuro-vascular remodeling in AT and are potential therapeutic targets in obesity.
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http://dx.doi.org/10.1038/s41467-018-07453-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6255810PMC
November 2018

Zic1 mRNA is transiently upregulated in subcutaneous fat of acutely cold-exposed mice.

J Cell Physiol 2019 03 20;234(3):2031-2036. Epub 2018 Oct 20.

Department of Experimental and Clinical Medicine, Center of Obesity, University of Ancona (Politecnica delle Marche), Ancona, Marche, Italy.

In the mammalian adipose organ cold exposure not only activates typical brown adipose tissue, but also induces browning, that is the formation of thermogenic multilocular adipocytes in white, or predominantly white, adipose depots such as subcutaneous fat. Unlike typical brown adipocytes, newly formed thermogenic adipocytes have been reported not to express the gene zinc finger of the cerebellum 1 (Zic1). Here, a time course approach enabled us to document a significant increase in Zic1 messenger RNA in inguinal subcutaneous fat from acutely (24 hr) cold-exposed mice, which was paralleled by an increase in multilocular and paucilocular uncoupling protein 1-positive adipocytes and in parenchymal noradrenergic innervation. This transient, depot-specific molecular signature was associated not to Zic1 promoter demethylation, but to chromatin remodeling through an H3K9me3 histone modification. These findings challenge the notion that Zic1 is exclusively expressed by typical brown adipocytes and suggest its involvement in brown adipocyte precursor differentiation and/or white-to-brown adipocyte transdifferentiation.
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http://dx.doi.org/10.1002/jcp.27301DOI Listing
March 2019

Adipose Organ Development and Remodeling.

Authors:
Saverio Cinti

Compr Physiol 2018 09 14;8(4):1357-1431. Epub 2018 Sep 14.

Professor of Human Anatomy, Director, Center of Obesity, University of Ancona (Politecnica delle Marche), Ancona, Italy.

During the last decades, research on adipose tissues has spread in parallel with the extension of obesity. Several observations converged on the idea that adipose tissues are organized in a large organ with endocrine and plastic properties. Two parenchymal components: white (WATs) and brown adipose tissues (BATs) are contained in subcutaneous and visceral compartments. Although both have endocrine properties, their function differs: WAT store lipids to allow intervals between meals, BAT burns lipids for thermogenesis. In spite of these opposite functions, they share the ability for reciprocal reversible transdifferentiation to tackle special physiologic needs. Thus, chronic need for thermogenesis induces browning and chronic positive energy balance induce whitening. Lineage tracing and data from explant studies strongly suggest other remodeling properties of this organ. During pregnancy and lactation breast WAT transdifferentiates into milk-secreting glands, composed by cells with abundant cytoplasmic lipids (pink adipocytes) and in the postlactation period pink adipocytes transdifferentiate back into WAT and BAT. The plastic properties of mature adipocytes are supported also by a liposecretion process in vitro where adult cell in culture transdifferentiate to differentiated fibroblast-like elements able to give rise to different phenotypes (rainbow adipocytes). In addition, the inflammasome system is activated in stressed adipocytes from obese adipose tissue. These adipocytes die and debris are reabsorbed by macrophages inducing a chronic low-grade inflammation, potentially contributing to insulin resistance and T2 diabetes. Thus, the plastic properties of this organ could open new therapeutic perspectives in the obesity-related metabolic disease and in breast pathologies. © 2018 American Physiological Society. Compr Physiol 8:1357-1431, 2018.
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http://dx.doi.org/10.1002/cphy.c170042DOI Listing
September 2018

Pink Adipocytes.

Authors:
Saverio Cinti

Trends Endocrinol Metab 2018 09 17;29(9):651-666. Epub 2018 Jul 17.

Department of Experimental and Clinical Medicine, Center of Obesity, University of Ancona (Politecnica delle Marche), Via Tronto 10a, 60020 Ancona, Italy. Electronic address:

Adipocytes are lipid-rich parenchymal cells contained in a very plastic organ, whose composition can undergo striking physiologic changes. In standard conditions the organ contains white and brown adipocytes which play opposite roles: lipid storage to meet metabolic requirements and lipid burning for thermogenesis, respectively. During chronic cold exposure, white adipocytes transdifferentiate to brown, to increase thermogenesis, whereas in conditions of chronic positive energy balance brown adipocytes transdifferentiate to white, to increase energy stores. During pregnancy, lactation, and post-lactation, subcutaneous white adipocytes convert to milk-producing glands formed by lipid-rich elements that can be defined as pink adipocytes. Recent fate-mapping data support the conversion of pink to brown adipocytes and the reversible conversion of brown adipocytes to myoepithelial cells of alveoli.
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http://dx.doi.org/10.1016/j.tem.2018.05.007DOI Listing
September 2018

Publisher Correction: Muscle and adipose tissue morphology, insulin sensitivity and beta-cell function in diabetic and nondiabetic obese patients: effects of bariatric surgery.

Sci Rep 2018 May 22;8(1):8177. Epub 2018 May 22.

CNR Institute of Clinical Physiology, Pisa, Italy.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-018-25221-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962565PMC
May 2018

Mitochondria Bound to Lipid Droplets Have Unique Bioenergetics, Composition, and Dynamics that Support Lipid Droplet Expansion.

Cell Metab 2018 04;27(4):869-885.e6

Division of Endocrinology, Department of Medicine, and Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Obesity Research Center, Department of Medicine, Boston University School of Medicine, Boston, MA, USA; Department of Clinical Biochemistry, School of Medicine, Ben Gurion University of The Negev, Beer-Sheva, Israel. Electronic address:

Mitochondria associate with lipid droplets (LDs) in fat-oxidizing tissues, but the functional role of these peridroplet mitochondria (PDM) is unknown. Microscopic observation of interscapular brown adipose tissue reveals that PDM have unique protein composition and cristae structure and remain adherent to the LD in the tissue homogenate. We developed an approach to isolate PDM based on their adherence to LDs. Comparison of purified PDM to cytoplasmic mitochondria reveals that (1) PDM have increased pyruvate oxidation, electron transport, and ATP synthesis capacities; (2) PDM have reduced β-oxidation capacity and depart from LDs upon activation of brown adipose tissue thermogenesis and β-oxidation; (3) PDM support LD expansion as Perilipin5-induced recruitment of mitochondria to LDs increases ATP synthase-dependent triacylglyceride synthesis; and (4) PDM maintain a distinct protein composition due to uniquely low fusion-fission dynamics. We conclude that PDM represent a segregated mitochondrial population with unique structure and function that supports triacylglyceride synthesis.
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http://dx.doi.org/10.1016/j.cmet.2018.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5969538PMC
April 2018

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

J Lipid Res 2018 05 29;59(5):784-794. Epub 2018 Mar 29.

Department of Experimental and Clinical Medicine and Center of Obesity, University of Ancona (Politecnica delle Marche)-United Hospitals, Ancona, Italy

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, β-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 ()-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 -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.
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http://dx.doi.org/10.1194/jlr.M079665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5928436PMC
May 2018