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Carmelo QUARTA

16 publication(s) since Septembre 2011:

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21/04/2020 | Int J Obes (Lond)   IF 4.4
Anti-obesity therapy with peripheral CB1 blockers: from promise to safe(?) practice.
Quarta C, Cota D

Pharmacological blockers of the cannabinoid receptor type-1 (CB1) have been considered for a long time as the holy grail of obesity pharmacotherapy. These agents were hastily released in the clinical setting, due to their clear-cut therapeutic efficacy. However, the first generation of these drugs, which were able to target both the brain and peripheral tissues, had serious neuropsychiatric effects, leading authorities to ban their clinical use. New peripherally restricted CB1 blockers, characterized by low brain penetrance, have been developed over the past 10 years. In preclinical studies, these molecules seem to overcome the neuropsychiatric negative effects previously observed with brain-penetrant CB1 inhibitors, while retaining or even outperforming their efficacy. The mechanisms of action of these peripherally restricted compounds are only beginning to emerge, and a balanced discussion of the risk/benefits ratio associated to their possible clinical use is urgently needed, in order to avoid repeating past mistakes. Here, we will critically discuss the advantages and the possible hidden threats associated with the use of peripheral CB1 blockers for the pharmacotherapy of obesity and its associated metabolic complications. We will address whether this novel pharmacological approach might 'compete' with current pharmacotherapies for obesity and diabetes, while also conceptualizing future CB1-based pharmacological trends that may significantly lower the risk/benefits ratio associated with the use of these drugs.

02/11/2019 | Neuroscience   IF 3.1
POMC Neurons Dysfunction in Diet-induced Metabolic Disease: Hallmark or Mechanism of Disease?
Quarta C, Fioramonti X, Cota D

One important lesson from the last decade of studies in the field of systemic energy metabolism is that obesity is first and foremost a brain disease. Hypothalamic neurons dysfunction observed in response to chronic metabolic stress is a key pathogenic node linking consumption of hypercaloric diets with body weight gain and associated metabolic sequelae. A key hypothalamic neuronal population expressing the neuropeptide Pro-opio-melanocortin (POMC) displays altered electrical activity and dysregulated neuropeptides production capacity after long-term feeding with hypercaloric diets. However, whether such neuronal dysfunction represents a consequence or a mechanism of disease, remains a subject of debate. Here, we will review and highlight emerging pathogenic mechanisms that explain why POMC neurons undergo dysfunctional activity in response to caloric overload, and critically address whether these mechanisms may be causally implicated in the physiopathology of obesity and of its associated co-morbidities.

02/2019 | nat metab
Functional identity of hypothalamic melanocortin neurons depends on Tbx3.
Quarta C, Fisette A, Xu Y, Collden G, Legutko B, Tseng YT, Reim A, Wierer M, De Rosa MC, Klaus V, Rausch R, Thaker VV, Graf E, Strom TM, Poher AL, Gruber T, Le Thuc O, Cebrian-Serrano A, Kabra D, Bellocchio L, Woods SC, Pflugfelder GO, Nogueiras R, Zeltser L, Grunwald Kadow IC, Moon A, Garcia-Caceres C, Mann M, Treier M, Doege CA, Tschop MH

Heterogeneous populations of hypothalamic neurons orchestrate energy balance via the release of specific signatures of neuropeptides. However, how specific intracellular machinery controls peptidergic identities and function of individual hypothalamic neurons remains largely unknown. The transcription factor T-box 3 (Tbx3) is expressed in hypothalamic neurons sensing and governing energy status, whereas human TBX3 haploinsufficiency has been linked with obesity. Here, we demonstrate that loss of Tbx3 function in hypothalamic neurons causes weight gain and other metabolic disturbances by disrupting both the peptidergic identity and plasticity of Pomc/Cart and Agrp/Npy neurons. These alterations are observed after loss of Tbx3 in both immature hypothalamic neurons and terminally differentiated mouse neurons. We further establish the importance of Tbx3 for body weight regulation in Drosophila melanogaster and show that TBX3 is implicated in the differentiation of human embryonic stem cells into hypothalamic Pomc neurons. Our data indicate that Tbx3 directs the terminal specification of neurons as functional components of the melanocortin system and is required for maintaining their peptidergic identity. In summary, we report the discovery of a key mechanistic process underlying the functional heterogeneity of hypothalamic neurons governing body weight and systemic metabolism.

23/10/2018 | Nat Commun   IF 12.1
Coordinated targeting of cold and nicotinic receptors synergistically improves obesity and type 2 diabetes.
Clemmensen C, Jall S, Kleinert M, Quarta C, Gruber T, Reber J, Sachs S, Fischer K, Feuchtinger A, Karlas A, Simonds SE, Grandl G, Loher D, Sanchez-Quant E, Keipert S, Jastroch M, Hofmann SM, Nascimento EBM, Schrauwen P, Ntziachristos V, Cowley MA, Finan B, Muller TD, Tschop MH

Pharmacological stimulation of brown adipose tissue (BAT) thermogenesis to increase energy expenditure is progressively being pursued as a viable anti-obesity strategy. Here, we report that pharmacological activation of the cold receptor transient receptor potential cation channel subfamily M member 8 (TRPM8) with agonist icilin mimics the metabolic benefits of cold exposure. In diet-induced obese (DIO) mice, treatment with icilin enhances energy expenditure, and decreases body weight, without affecting food intake. To further potentiate the thermogenic action profile of icilin and add complementary anorexigenic mechanisms, we set out to identify pharmacological partners next to icilin. To that end, we specifically targeted nicotinic acetylcholine receptor (nAChR) subtype alpha3beta4 (alpha3beta4), which we had recognized as a potential regulator of energy homeostasis and glucose metabolism. Combinatorial targeting of TRPM8 and nAChR alpha3beta4 by icilin and dimethylphenylpiperazinium (DMPP) orchestrates synergistic anorexic and thermogenic pathways to reverse diet-induced obesity, dyslipidemia, and glucose intolerance in DIO mice.

11/08/2016 | Cell   IF 38.6
Astrocytic Insulin Signaling Couples Brain Glucose Uptake with Nutrient Availability.
Garcia-Caceres C, Quarta C, Varela L, Gao Y, Gruber T, Legutko B, Jastroch M, Johansson P, Ninkovic J, Yi CX, Le Thuc O, Szigeti-Buck K, Cai W, Meyer CW, Pfluger PT, Fernandez AM, Luquet S, Woods SC, Torres-Aleman I, Kahn CR, Gotz M, Horvath TL, Tschop MH

We report that astrocytic insulin signaling co-regulates hypothalamic glucose sensing and systemic glucose metabolism. Postnatal ablation of insulin receptors (IRs) in glial fibrillary acidic protein (GFAP)-expressing cells affects hypothalamic astrocyte morphology, mitochondrial function, and circuit connectivity. Accordingly, astrocytic IR ablation reduces glucose-induced activation of hypothalamic pro-opio-melanocortin (POMC) neurons and impairs physiological responses to changes in glucose availability. Hypothalamus-specific knockout of astrocytic IRs, as well as postnatal ablation by targeting glutamate aspartate transporter (GLAST)-expressing cells, replicates such alterations. A normal response to altering directly CNS glucose levels in mice lacking astrocytic IRs indicates a role in glucose transport across the blood-brain barrier (BBB). This was confirmed in vivo in GFAP-IR KO mice by using positron emission tomography and glucose monitoring in cerebral spinal fluid. We conclude that insulin signaling in hypothalamic astrocytes co-controls CNS glucose sensing and systemic glucose metabolism via regulation of glucose uptake across the BBB.


05/2016 | Diabetologia   IF 7.5
Renaissance of leptin for obesity therapy.
Quarta C, Sanchez-Garrido MA, Tschop MH, Clemmensen C

Diet-induced obesity and its metabolic comorbidities constitute an overwhelming health crisis and there is an urgent need for safe and effective pharmacological interventions. Being largely shelved for decades, scientists are now revisiting the anti-obesity virtues of leptin. Whereas it remains evident that leptin as a stand-alone therapy is not an effective approach, the potential for employing sensitising pharmacology to unleash the weight-lowering properties of leptin has injected new hope into the field. Fascinatingly, these leptin-sensitising agents seem to act via distinct metabolic pathways and may thus, in parallel with their clinical development, serve as important research tools to progress our understanding of the molecular, physiological and behavioural pathways underlying energy homeostasis and obesity pathophysiology. This review summarises a presentation given at the 'Is leptin coming back?' symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Thomas Meek and Gregory Morton, DOI: 10.1007/s00125-016-3898-3 , and by Gerald Shulman and colleagues, DOI: 10.1007/s00125-016-3909-4 ) and an overview by the Session Chair, Ulf Smith (DOI: 10.1007/s00125-016-3894-7 ).

29/02/2016 | Nat Commun   IF 12.1
Hypothalamic leptin action is mediated by histone deacetylase 5.
Kabra DG, Pfuhlmann K, Garcia-Caceres C, Schriever SC, Casquero Garcia V, Kebede AF, Fuente-Martin E, Trivedi C, Heppner K, Uhlenhaut NH, Legutko B, Kabra UD, Gao Y, Yi CX, Quarta C, Clemmensen C, Finan B, Muller TD, Meyer CW, Paez-Pereda M, Stemmer K, Woods SC, Perez-Tilve D, Schneider R, Olson EN, Tschop MH, Pfluger PT

Hypothalamic leptin signalling has a key role in food intake and energy-balance control and is often impaired in obese individuals. Here we identify histone deacetylase 5 (HDAC5) as a regulator of leptin signalling and organismal energy balance. Global HDAC5 KO mice have increased food intake and greater diet-induced obesity when fed high-fat diet. Pharmacological and genetic inhibition of HDAC5 activity in the mediobasal hypothalamus increases food intake and modulates pathways implicated in leptin signalling. We show HDAC5 directly regulates STAT3 localization and transcriptional activity via reciprocal STAT3 deacetylation at Lys685 and phosphorylation at Tyr705. In vivo, leptin sensitivity is substantially impaired in HDAC5 loss-of-function mice. Hypothalamic HDAC5 overexpression improves leptin action and partially protects against HFD-induced leptin resistance and obesity. Overall, our data suggest that hypothalamic HDAC5 activity is a regulator of leptin signalling that adapts food intake and body weight to our dietary environment.

28/01/2016 | Cell   IF 38.6
Epigenetic ON/OFF Switches for Obesity.
Quarta C, Schneider R, Tschop MH

Heritable epigenetic mechanisms might contribute to the worldwide increase in the prevalence of obesity. Dalgaard et al. identify an epigenetic molecular switch that controls body weight control. The discovery suggests the existence of mammalian polyphenism in energy metabolism and might have implications for strategies to limit the obesity epidemic.

11/2014 | Faseb J   IF 5
Direct activating effects of adrenocorticotropic hormone (ACTH) on brown adipose tissue are attenuated by corticosterone.
van den Beukel JC, Grefhorst A, Quarta C, Steenbergen J, Mastroberardino PG, Lombes M, Delhanty PJ, Mazza R, Pagotto U, van der Lely AJ, Themmen AP

Brown adipose tissue (BAT) and brown-like cells in white adipose tissue (WAT) can dissipate energy through thermogenesis, a process mediated by uncoupling protein 1 (UCP1). We investigated whether stress hormones ACTH and corticosterone contribute to BAT activation and browning of WAT. ACTH and corticosterone were studied in male mice exposed to 4 or 23 degrees C for 24 h. Direct effects were studied in T37i mouse brown adipocytes and primary cultured murine BAT and inguinal WAT (iWAT) cells. In vivo effects were studied using (18)F-deoxyglucose positron emission tomography. Cold exposure doubled serum ACTH concentrations (P=0.03) and fecal corticosterone excretion (P=0.008). In T37i cells, ACTH dose-dependently increased Ucp1 mRNA (EC50=1.8 nM) but also induced Ucp1 protein content 88% (P=0.02), glycerol release 32% (P=0.03) and uncoupled respiration 40% (P=0.003). In cultured BAT and iWAT, ACTH elevated Ucp1 mRNA by 3-fold (P=0.03) and 3.7-fold (P=0.01), respectively. In T37i cells, corticosterone prevented induction of Ucp1 mRNA and Ucp1 protein by both ACTH and norepinephrine in a glucocorticoid receptor (GR)-dependent fashion. ACTH and GR antagonist RU486 independently doubled BAT (18)F-deoxyglucose uptake (P=0.0003 and P=0.004, respectively) in vivo. Our results show that ACTH activates BAT and browning of WAT while corticosterone counteracts this.