Landre, T. | bioRxiv Science

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↗

bioRxiv2025

Hepatocyte FGF21 is not required for fasting-induced metabolic responses but guides protein appetite after energy depletion

Fasting initiates a coordinated metabolic response to preserve energy balance. As glycogen stores are depleted, the body transitions to mobilizing fatty acids from adipose tissue and generating ketone bodies in the liver to sustain the function of vital organs. A network of hormonal signals and transcriptional programs coordinate these adaptations. Among these, the hepatokine fibroblast growth factor 21 (FGF21) is strongly upregulated during fasting and has been proposed as a key mediator of the fasting response. To investigate the physiological functions of FGF21, we studied mice with hepatocyte-specific deletion of Fgf21. Although the liver is the primary source of circulating FGF21 during fasting, its absence in hepatocytes did not alter typical fasting-induced gene expression or key metabolic pathways such as hepatic gluconeogenesis, adipose tissue lipolysis, or ketone production. Instead, we uncovered a distinct role for FGF21 in promoting protein appetite following a fast. These findings challenge the conventional view of hepatocyte-produced FGF21 as a fasting-acting hormone and reveal a more specialized function in guiding nutrient selection after energy depletion.

physiology↗