Ben Fradj, S. | Search bioRxiv

bioRxiv2026

Postprandial hypertriglyceridemia activates microglia to promote satiety via an ASC dependent signaling.

Reactive microglia are commonly considered neurotoxic and detrimental for brain functioning. Chronic consumption of a high-fat diet strongly activates microglia, disrupts the central control of energy metabolism, contributes to obesity, and promotes cognitive decline. In this study we report an unexpected beneficial function of microglia reaction at the time scale of a meal, whereby they promote satiety in a macronutrient-dependent manner. We show that murine microglia react to ingested dietary fat within three hours. Specifically, postprandial hypertriglyceridemia induced microglial hyper-ramification alongside with a transcriptional reprogramming promoting communication with neurons. This effect occurs in discrete brain areas, including the hypothalamus and the brainstem, which control hunger. Remarkably, microglia-specific genetic ablation of Apoptosis-associated Speck-like protein containing a CARD (named ASC), a master regulator of metabolism, immune function and cell shape, profoundly alters satiety following high-fat food consumption. These results reveal that microglia engage an immune signaling pathway to rapidly alert the neural circuits and activate an anorectic response that limits overconsumption of dietary fat. Unexpectedly, this regulatory process is sexually dimorphic, present in males only. Furthermore, we found that the postprandial microglial reaction is bypassed during obesity, providing a new therapeutic target to treat maladaptive eating disorders.

neuroscience↗

bioRxiv2024

Yo-yo dieting deregulates feeding behavior in mice via the induction of durable gut dysbiosis

Background & AimsAlternating periods of excessive and restrained eating results in weight cycling, a known risk factor for eating behavior dysregulation such as binge eating. Diet alternation also induces changes in intestinal microbiota composition. We tested the hypothesis that recurrent diet alternation alters hedonic feeding regulation by changing either or both intestinal microbiota and brain homeostasis in mouse. MethodsC57BL/6 mice underwent 3 cycles of 1 week of western diet (WD, 45% kcal from fat) separated by 2 weeks of chow diet (CYCL group) or staid under chow diet (CTRL group). Food intake was monitored after each dietary change. Striatum, hypothalamus, brainstem and caecal content were collected before the third WD introduction in CYCL mice and in CTRL mice. Microbiota transfer from CYCL or CTRL mice into naive recipient mice was performed to investigate whether gut microbiota per se could explain differences in eating behavior during weight cycling. ResultsDiet alternation in CYCL mice resulted in weight cycling, with enhanced weight gain upon each WD feeding phase. CYCL mice increased their energy intake specifically during the first hours following WD re-introduction, reminiscent of binge-eating episodes. Expression of reward-related genes in the striatum and thickness of the astro-glial barrier in the brain stem were enhanced in CYCL compared to CTRL mice. Diet alternation also induced caecal dysbiosis in CYCL mice. Gut microbiota transfer from CYCL mice to naive recipient mice recapitulated the altered eating behavior upon WD exposure. ConclusionsAlternation between high-energy and standard diet durably remodels the gut microbiota and the brain towards a profile associated with an increase in hedonic appetite. Using gut microbiota transfer, we established that this microbiota signature affects hedonic feeding regulation. These results open the ways to microbiota-targeted strategies to prevent development of eating disorders in weight cycling patients.

physiology↗