Carmelo QUARTA

19 publication(s) depuis Septembre 2011:

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19/04/2021 | Cell Metab   IF 21.6
Hypothalamic bile acid-TGR5 signaling protects from obesity.
Castellanos-Jankiewicz A, Guzman-Quevedo O, Fenelon VS, Zizzari P, Quarta C, Bellocchio L, Tailleux A, Charton J, Fernandois D, Henricsson M, Piveteau C, Simon V, Allard C, Quemener S, Guinot V, Hennuyer N, Perino A, Duveau A, Maitre M, Leste-Lasserre T, Clark S, Dupuy N, Cannich A, Gonzales D, Deprez B, Mithieux G, Dombrowicz D, Backhed F, Prevot V, Marsicano G, Staels B, Schoonjans K, Cota D

Bile acids (BAs) improve metabolism and exert anti-obesity effects through the activation of the Takeda G protein-coupled receptor 5 (TGR5) in peripheral tissues. TGR5 is also found in the brain hypothalamus, but whether hypothalamic BA signaling is implicated in body weight control and obesity pathophysiology remains unknown. Here we show that hypothalamic BA content is reduced in diet-induced obese mice. Central administration of BAs or a specific TGR5 agonist in these animals decreases body weight and fat mass by activating the sympathetic nervous system, thereby promoting negative energy balance. Conversely, genetic downregulation of hypothalamic TGR5 expression in the mediobasal hypothalamus favors the development of obesity and worsens established obesity by blunting sympathetic activity. Lastly, hypothalamic TGR5 signaling is required for the anti-obesity action of dietary BA supplementation. Together, these findings identify hypothalamic TGR5 signaling as a key mediator of a top-down neural mechanism that counteracts diet-induced obesity.

25/02/2021 | nat metab
POMC neuronal heterogeneity in energy balance and beyond: an integrated view.
Quarta C, Claret M, Zeltser LM, Williams KW, Yeo GSH, Tschop MH, Diano S, Bruning JC, Cota D

Hypothalamic AgRP and POMC neurons are conventionally viewed as the yin and yang of the body's energy status, since they act in an opposite manner to modulate appetite and systemic energy metabolism. However, although AgRP neurons' functions are comparatively well understood, a unifying theory of how POMC neuronal cells operate has remained elusive, probably due to their high level of heterogeneity, which suggests that their physiological roles might be more complex than initially thought. In this Perspective, we propose a conceptual framework that integrates POMC neuronal heterogeneity with appetite regulation, whole-body metabolic physiology and the development of obesity. We highlight emerging evidence indicating that POMC neurons respond to distinct combinations of interoceptive signals and food-related cues to fine-tune divergent metabolic pathways and behaviours necessary for survival. The new framework we propose reflects the high degree of developmental plasticity of this neuronal population and may enable progress towards understanding of both the aetiology and treatment of metabolic disorders.

03/11/2020 | Diabetes   IF 7.7
CB1 and GLP-1 Receptors Cross-Talk Provides New Therapies for Obesity.
Zizzari P, He R, Falk S, Bellocchio L, Allard C, Clark S, Lest, Quarta C

GLP-1 receptor (GLP-1R) agonists effectively improve glycemia and body weight in patients with type 2 diabetes and obesity, but have limited weight-lowering efficacy and minimal insulin sensitizing action. In preclinical models, peripherally-restricted cannabinoid-1 receptor (CB1R) inhibitors, which are devoid of the neuropsychiatric side-effects observed with brain-penetrant CB1R blockers, ameliorate obesity and its multiple metabolic complications. Using mouse models with genetic loss of CB1R or GLP-1R, we demonstrate that these two metabolic receptors modulate food intake and body weight via reciprocal functional interactions. In diet-induced obese mice, the co-administration of a peripheral CB1R inhibitor with long-acting GLP-1R agonists achieves greater reduction in body weight and fat mass than monotherapies, by promoting negative energy balance. This co-treatment also results in larger improvements in systemic and hepatic insulin action, systemic dyslipidemia, and reduction of hepatic steatosis. Thus, peripheral CB1R blockade may allow safely potentiating the anti-obesity and anti-diabetic effects of currently available GLP-1R agonists.

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 3.2
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 12.4
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 28.7
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 6.2
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 ).