Biology subjects

Zizzari, P.

Publications and source records attributed to Zizzari, P..

6 recordsLinked to original sources

bioRxiv2026

A Female-Specific Microglial Redox Program Gates Susceptibility to Obesity

Chronic consumption of energy-dense, high-fat foods persistently exposes hypothalamic circuits that govern body weight to nutrient excess, progressively altering their activity and thereby promoting obesity. Microglia, the brain resident immune cells, sense circulating lipids, but how their intracellular metabolic programs adapt to chronic dietary excess, and how this contributes to obesity risk, is unclear. Here, we reveal a sex-dependent control of calorie overload by hypothalamic microglial cells. In females, but not males, microglia engage a protective metabolic program with increased antioxidant capacity and mitochondrial network remodeling, conferring resistance to early weight gain. Over time, activation of mTORC1 signaling in microglia disrupts mitochondrial functions and dismantles this transient resilience, culminating in weight gain. These findings identify microglial mTORC1 as a sex-specific switch between resilience and vulnerability to obesity and position microglial metabolism as a tractable target for sex-informed weight control.

neuroscience↗

bioRxiv2026

Extracellular DNASE1L3 dysfunction fuels obesity-driven inflammation and metabolic syndrome

Obesity, a global health crisis affecting 16% of the world population, is characterized by chronic inflammation that contributes to health complications such as type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD). Emerging evidence suggests that self-DNA released from dying cells aberrantly activates inflammatory responses during obesity. However, the role of extracellular deoxyribonucleases (DNASEs), which at steady state regulate abundance of extracellular self-DNA, remains poorly understood in this context. Here, we show that individuals with obesity exhibit elevated levels of circulating cell-free DNA (cfDNA) with a distinctive end-motif signature, anti-DNASE1L3 autoantibodies and a reduction in circulating DNASE activity. These cfDNA alterations correlate with the severity of obesity and can be corrected by therapeutic intervention such as bariatric surgery. Similarly, mice fed a high-fat diet (HFD) displayed increased cfDNA levels and decreased DNASE activity. Genetic deficiency of the extracellular nuclease DNASE1L3 in mice worsened HFD-induced metabolic complications, including glucose intolerance, insulin resistance, MASLD, and metabolic tissue inflammation. Conversely, targeted supplementation of DNASE1L3 in the liver using adeno-associated viral vectors protected obese mice from developing MASLD and liver inflammation. These findings uncover a novel role of DNASE1L3 in controlling obesity-associated inflammation and its potential therapeutic use for preventing metabolic disease.

pathology↗

bioRxiv2024

DEFICIENCY OF THE NUTRIENT SENSOR CPT1c IN SF1 NEURONS DISRUPTS THE ENDOCANNABINOID SYSTEM RESULTING IN COMPROMISED SATIETY AND FUEL SELECTION UPON FAT INTAKE

The SF1 neurons of the ventromedial hypothalamus (VMH) are pivotal in governing body weight and adiposity, particularly in response to a high-fat diet (HFD). Previous studies have shown that the activation of SF1 neurons induces satiety, increases energy expenditure, and promotes the preferential use of fats as energy substrate. Furthermore, SF1 neurons are necessary for recovering from insulin-induced hypoglycemia. Here we demonstrate the essential role of the nutritional sensor CPT1c in the activation of SF1 neurons by dietary fats. Mice deficient in CPT1C in SF1 neurons (SF1-CPT1c-KO) are unable to adjust their caloric intake during the initial exposure to a HFD. This is associated with an impaired metabolic transition in the liver, muscle, and adipose tissue, despite a normal response to a glucose or insulin challenge. During chronic HFD exposure, SF1-CPT1c-KO mice are more prone to obesity and glucose intolerance than controls. CPT1c deficiency in SF1 neurons also leads to alterations in hypothalamic endocannabinoid levels and their metabolism. Our findings posit CPT1C in SF1 neurons as a sensor for dietary fats, regulating satiety responses and nutrient partitioning likely through the modulation of the endocannabinoid system.

neuroscience↗

bioRxiv2020

The GhsrQ343X allele favors the storage of fat by acting on nutrient partitioning

The Growth Hormone Secretagogue Receptor (GHSR) mediates key properties of the gut hormone ghrelin on metabolism and behavior. Nevertheless, most recent observations also support that the GHSR is a constitutively active G protein-coupled receptor endowed of a sophisticated tuning involving a balance of endogenous ligands. Demonstrating the feasibility of shifting GHSR canonical signaling in vivo, we previously reported that a model with enhanced sensitivity to ghrelin (GhsrQ343X mutant rats) developed fat accumulation and glucose intolerance. Herein, we investigated the contribution of energy homeostasis to the onset of this phenotype, as well as behavioral responses to feeding or pharmacological challenges, by comparing GhsrM/M rats to wild-type littermate rats 1) as freely behaving animals using an automated system to monitor simultaneously energy intake and expenditure, respiratory exchanges and voluntary activity and 2) in feeding and locomotor paradigms. Herein, GhsrM/M rats showed enhanced locomotor response to a GHSR agonist while locomotor or anorexigenic responses to amphetamine or cabergoline (dopamine receptor 2 agonist), respectively, were preserved. Ad libitum fed GhsrM/M rats consumed and conditioned for sucrose similarly to littermate control rats. In calorie-restricted conditions, GhsrM/M rats retained food anticipatory activity and maintained better their body weight and glycemia. Finally, prior to fat accumulation GhsrM/M rats showed shifted fuel preference towards carbohydrates utilization without alterations of energy intake, energy expenditure or physical activity. Overall, the present study provides proof of concept that shifted GHSR signaling can operate a specific alteration in nutrient partitioning resulting in modified balance of carbohydrate/lipid utilization.

physiology↗

bioRxiv2020

POMC neurons functional heterogeneity relies on mTORC1 signaling

Hypothalamic Pro-opiomelanocortin (POMC) neurons are classically known to trigger satiety. However, they encompass heterogeneous subpopulations whose functions are unknown. Here we show that POMC neurons releasing GABA, glutamate or both neurotransmitters possess distinct spatial distribution, molecular signatures and functions. Functional specificity of these subpopulations relies on the energy sensor mechanistic Target of Rapamycin Complex 1 (mTORC1), since pharmacological blockade of mTORC1, by mimicking a cellular negative energy state, simultaneously inhibited POMC/glutamatergic and activated POMC/GABAergic neurons. Chemogenetics and conditional deletion of mTORC1 then demonstrated that mTORC1 blockade in POMC neurons causes hyperphagia. This is due to decreased POMC-derived anorexigenic -melanocyte-stimulating hormone and the recruitment of POMC/GABAergic neurotransmission, which is restrained by cannabinoid type 1 receptor signaling. Genetic inhibition of glutamate release from POMC neurons also produced hyperphagia, recapitulating the phenotype caused by mTORC1 blockade. Altogether, these findings pinpoint the molecular mechanisms engaged by POMC neurons to oppositely control feeding, thereby challenging conventional views about their functions.

neuroscience↗

bioRxiv2019

Top-down control of water intake by the endocannabinoid system

Water intake is regulated by neocortical top-down circuits, but their identity and the cellular mechanisms involved are scantly known. Here, we show that endogenous activation of type-1 cannabinoid receptors (CB1) promotes water intake and that endocannabinoid modulation of excitatory projections from the anterior cingulate cortex to the basolateral amygdala is sufficient to guarantee physiological drinking. These data reveal a new circuit involved in the homeostatic control of water intake.

neuroscience↗