Biology subjects

Brito, D. V.

Publications and source records attributed to Brito, D. V..

3 recordsLinked to original sources

bioRxiv2026

Hypothalamic CYP46A1 cholesterol metabolism regulates diet-induced obesity

Obesity is a growing global health challenge which affects over 38% of the population and increases the risk of developing metabolic disorders. Effective long-term treatment options remain limited and often lead to significant side effects. The hypothalamus plays a central role in metabolic regulation by integrating peripheral and central signals to maintain energy homeostasis. While the hypothalamus regulates peripheral lipid metabolism, the role of lipid metabolic pathways within the hypothalamus itself remains unclear. Therefore, the molecular mechanisms linking hypothalamic activity to the development of obesity remain poorly understood. Given that cholesterol is the most abundant brain lipid, we investigated molecular players involved in its local regulation. Here, we identify the rate-limiting enzyme for brain cholesterol degradation, Cyp46a1, as a critical regulator of diet-induced obesity. We show that Cyp46a1 expression is significantly reduced in the hypothalamus of C57BL/6J mice exposed to a high-fat diet, suggesting a role in metabolic dysregulation. We used recombinant Adeno-Associated Viruses (AAV) to modulate Cyp46a1 expression in the arcuate nucleus, a key hypothalamic region regulating energy balance. We evaluated longitudinal changes in body weight, adipocyte size, PPAR-{gamma} expression, and hepatic lipid accumulation and pancreatic histopathology in mice undergoing chow or high fat diets. These experiments demonstrated that hypothalamic Cyp46a1 regulates body weight, adipocyte size, and hepatic and pancreatic histopathology. Conversely, CYP46A1 overexpression protects against high-fat diet-induced obesity and improves glucose homeostasis and insulin sensitivity, likely via crosstalk with hepatic and pancreatic function. Moreover, we found that hypothalamic CYP46A1 expression selectively modulates gut microbiota composition, linking this enzyme to the microbiota-gut-brain axis. Finally, we found that Cyp46a1 levels influence cognitive and motor performance, suggesting broader physiological relevance. Collectively, our findings reveal a previously unrecognized role of hypothalamic Cyp46a1 and cholesterol pathway control in obesity pathophysiology and metabolic homeostasis. These findings identify hypothalamic Cyp46a1 as a promising therapeutic target for obesity and its related comorbidities.

neuroscience↗

bioRxiv2020

Engram reactivation during memory retrieval predicts long-term memory performance in aged mice

Age-related cognitive decline preferentially targets long-lasting episodic memories that require intact hippocampal function. Memory traces (or engrams) are believed to be encoded within the neurons activated during learning (neuronal ensembles), and recalled by reactivation of the same population. However, whether engram reactivation dictates memory performance late in life is not known. Here, we labelled neuronal ensembles formed during object location recognition learning in the dentate gyrus, and analyzed the reactivation of this population by long-term memory recall in young adult, cognitively impaired-and unimpaired-aged mice. We found that reactivation of memory-encoding neuronal ensembles at long-term memory recall was disrupted in impaired but not unimpaired-aged mice. Furthermore, we showed that the memory performance in the aged population correlated with the degree of engram reactivation at long-term memory recall. Overall, our data implicates recall-induced engram reactivation as a prediction factor of memory performance in aging. Moreover, our findings suggest impairments in neuronal ensemble stabilization and/or reactivation as an underlying mechanism in age-dependent cognitive decline.

neuroscience↗

bioRxiv2020

Modeling human age-associated increase in Gadd45γ expression leads to spatial recognition memory impairments in young adult mice

Aging is associated with the progressive decay of cognitive function. Hippocampus-dependent processes, such as the formation of spatial memory, are particularly vulnerable to aging. Currently, the molecular mechanisms responsible for age-dependent cognitive decline are largely unknown. Here, we investigated the expression and function of the growth arrest DNA damage gamma (Gadd45{gamma}) during aging and cognition. We report that Gadd45{gamma} expression is increased in the hippocampus of aged humans and that Gadd45{gamma} overexpression in the young adult mouse hippocampus compromises cognition. Moreover, Gadd45{gamma} overexpression in hippocampal neurons disrupted CREB signaling and the expression of well-established activity-regulated genes. This work shows that Gadd45{gamma} expression is tightly controlled in the hippocampus and its disruption may be a mechanism contributing to age-related cognitive impairments observed in humans.

neuroscience↗