Marcia Barbosa Aguila

A neuroinflamação tem sido reconhecida como um eixo central na fisiopatologia do envelhecimento cerebral e das doenças neurodegenerativas. O envelhecimento populacional, associado à elevada prevalência de doenças cardiometabólicas, tem contribuído para o aumento expressivo das demências, incluindo a doença de Alzheimer e a doença de Parkinson. Evidências experimentais e humanas demonstram que a neuroinflamação crônica de baixo grau, caracterizada pela ativação persistente da micróglia e pela reatividade dos astrócitos, desempenha papel determinante na disfunção sináptica, na perda de plasticidade neural, na reorganização patológica dos circuitos neuronais e no declínio cognitivo progressivo. Em nível molecular, a liberação sustentada de citocinas pró-inflamatórias, o estresse oxidativo, a disfunção mitocondrial e a ativação de vias inflamatórias intracelulares estabelecem um ciclo autoperpetuante de inflamação e vulnerabilidade neuronal. Do ponto de vista funcional, esses processos afetam preferencialmente regiões com alta demanda metabólica e plasticidade, como o hipocampo e o córtex pré-frontal, resultando em déficits de memória, atenção, funções executivas e cognição social. Apesar das diferenças clínicas e anatômicas entre as doenças neurodegenerativas, a neuroinflamação emerge como um mecanismo convergente em condições como a doença de Alzheimer, a doença de Parkinson, a esclerose lateral amiotrófica e a esclerose múltipla. Nesse contexto, estratégias terapêuticas voltadas à modulação da inflamação cerebral têm ganhado destaque. Agonistas do receptor do peptídeo semelhante ao glucagon tipo 1 e ácidos graxos ômega-3 (EPA e DHA) apresentam potencial neuroprotetor ao modularem a ativação glial, reduzirem citocinas pró-inflamatórias e estresse oxidativo, e preservarem a função mitocondrial e a plasticidade sináptica. Entretanto, limitações translacionais ainda impõem desafios à ampla aplicação clínica.

Objective: To investigate the impact of estrogen deficiency on metabolic dysfunction-associated steatotic liver disease progression and evaluate the therapeutic potential of tirzepatide (Tzp), a dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist, in a murine model of postmenopausal metabolic dysfunction. Methods: Female C57BL/6J mice were divided into obese-diabetic (Od) and ovariectomized Od groups, along with lean controls (control, CO). After 12 weeks of dietary intervention, mice received daily Tzp (10 nmol/kg) or vehicle for four weeks. Comprehensive assessments included plasma biochemistry, liver histopathology, AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) complex 1 signaling analysis, and hepatic gene expressions. Results: Od mice developed severe liver pathology, showing 2-3 fold increases in fat accumulation markers, extensive steatosis with hepatocyte ballooning, and 3-4 fold elevated inflammatory markers. Ovariectomy aggravated these effects, increasing fibrosis markers by 2.4-fold and apoptosis signals. Tzp reduced fat deposition by 50%-70%, inflammation by 60%-70%, and fibrosis by 55%. Molecular analyses revealed Tzp restored metabolic balance by: (1) normalizing key energy-sensing pathways (1.5-2 fold AMPK activation; 50% mTOR reduction), (2) reducing fat synthesis signals by 50%-60%, and (3) enhancing fat breakdown pathways (2-2.5 fold increase). Antioxidant defenses were fully restored to normal levels. Principal component analysis demonstrated metabolic improvement, with treated animals showing gene expression patterns closer to healthy controls. Conclusion: Estrogen deficiency synergizes with metabolic dysfunction to aggravate metabolic dysfunction-associated steatotic liver disease progression through AMPK/mTOR pathway dysregulation. Tzp demonstrates comprehensive hepatoprotective effects, ameliorating steatosis, inflammation, and fibrosis while restoring metabolic homeostasis in this model of postmenopausal liver disease.

We hypothesized that melatonin (Mel) supplementation may offer therapeutic benefits for obesity, particularly in women. Therefore, the study evaluated Mel's effects on white adipose tissue (WAT) in diet‐induced obese female mice. Four‐week‐old C57BL/6 females were assigned to either a control diet (C group) or a high‐fat diet (HF group) for 6 weeks (n = 20/group). Following this, Mel was administered (10 mg/kg/day) for 8 weeks (n = 10/group), resulting in four groups: C, CMel, HF, and HFMel. The HF group developed obesity. HFMel displayed reduced fat pad size, lower plasma insulin, and improved glucose tolerance and insulin resistance compared to HF. In ovarian WAT (oWAT), HFMel versus HF showed reduced pro‐inflammatory markers, less endoplasmic reticulum (ER) stress, and smaller adipocyte size. In subcutaneous WAT (sWAT), HFMel versus HF demonstrated increased adipocyte multiloculation, higher uncoupling protein‐1 expression, and elevated thermogenic gene expression. Principal component analysis of gene expressions in oWAT and sWAT revealed significant differences: in oWAT, ER stress and inflammation markers were linked to the HF group, while HFMel and CMel clustered together, indicating a beneficial Mel effect. In sWAT, HFMel and CMel clustered on the opposite side of HF, which is associated with thermogenic gene expressions. In conclusion, the findings demonstrate that Mel supplementation in obese female mice, even when maintained on an HF diet, effectively modulated weight gain and reduced ovarian and subcutaneous fat accumulation. Mel supplementation positively influenced insulin resistance, inflammation, and ER stress while promoting thermogenesis in WAT in obese female mice.