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<p>Obesity is a chronic neurometabolic disorder characterized by low-grade systemic inflammation, adipose tissue dysfunction, and impaired central regulation of energy balance. This review summarizes mechanistic and translational evidence showing that diet-induced changes in the gut microbiota contribute to altered signaling along the gut-hypothalamus-adipose tissue axis. Obesogenic diets modify microbial metabolic activity by reducing short-chain fatty acid production, altering bile acid composition, and increasing endotoxin-related signaling, which together impair intestinal barrier function and promote metabolic endotoxemia. These signals reach the brain through endocrine (GLP-1, PYY), immune (cytokines, TLR4-dependent pathways), and neural (vagal/neuropod) routes, and are associated with hypothalamic microinflammation, impaired leptin and insulin signaling, and a persistent orexigenic drive. At the same time, adipose tissue undergoes hypertrophy and immunometabolic remodeling, reinforcing systemic inflammation and central dysregulation in a self-sustaining feedback loop. Incretin-based therapies, including GLP-1 and dual GIP/GLP-1 receptor agonists, act in part through modulation of this axis, including microbiota-related mechanisms. However, the frequent regain of weight after treatment discontinuation indicates that central and peripheral circuits are not fully reprogrammed. Viewing obesity as a disorder of disrupted inter-organ signaling highlights microbial metabolic pathways as relevant targets for more durable metabolic improvement.</p>

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From diet to hypothalamic dysfunction: Neuroanatomical and hormonal integration of the microbiota-hypothalamus-adipose tissue axis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月21日

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  • Helena Dias de Freitas Queiroz Barros,
  • Breno Picin Casagrande,
  • Diana Dias Araújo,
  • Thais Antonio Jose Mutran,
  • Monica Marques Telles,
  • Debora Estadella,
  • Luciana Pellegrini Pisani

摘要

Obesity is a chronic neurometabolic disorder characterized by low-grade systemic inflammation, adipose tissue dysfunction, and impaired central regulation of energy balance. This review summarizes mechanistic and translational evidence showing that diet-induced changes in the gut microbiota contribute to altered signaling along the gut-hypothalamus-adipose tissue axis. Obesogenic diets modify microbial metabolic activity by reducing short-chain fatty acid production, altering bile acid composition, and increasing endotoxin-related signaling, which together impair intestinal barrier function and promote metabolic endotoxemia. These signals reach the brain through endocrine (GLP-1, PYY), immune (cytokines, TLR4-dependent pathways), and neural (vagal/neuropod) routes, and are associated with hypothalamic microinflammation, impaired leptin and insulin signaling, and a persistent orexigenic drive. At the same time, adipose tissue undergoes hypertrophy and immunometabolic remodeling, reinforcing systemic inflammation and central dysregulation in a self-sustaining feedback loop. Incretin-based therapies, including GLP-1 and dual GIP/GLP-1 receptor agonists, act in part through modulation of this axis, including microbiota-related mechanisms. However, the frequent regain of weight after treatment discontinuation indicates that central and peripheral circuits are not fully reprogrammed. Viewing obesity as a disorder of disrupted inter-organ signaling highlights microbial metabolic pathways as relevant targets for more durable metabolic improvement.