Denis, I. | Search bioRxiv

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↗

bioRxiv2024

CRE mice exhibit hyperactive and impulsive behavior affecting their learning and retention performances

CRE recombinase is a protein that recognizes and mediates site-specific recombination between loxP site sequences. The Cre/loxP recombination system has become a useful tool for genetic manipulation. Spatial regulation of recombination can be achieved by using cell type-specific promoters that drive expression of CRE in the tissue of interest. The temporal regulation can be obtained with CreER recombinase, which consists of Cre fused to mutated hormone-binding domain of the estrogen receptor (ER). In the more improved versions of the construct, the CRE-mediated gene regulation can be controlled both spatially and temporally, by combining tissue-specific expression of a CreER recombinase with its tamoxifen-dependent activity. We recently generated and characterized an astrocyte specific mutant of the lipolysis-stimulated lipoprotein receptor lsr gene by crossing Glast ERT2 mice with floxed lsr mice (El Hajj et al., 2022). During the behavioral analysis of generated mice, we identified specific hyperactive traits in the Glast ERT2 mice (CRE mice) that prevented them from being used as a control group. Here we further assessed the hyperactive trait of those CRE mice using a battery of behavioral tests. We showed that CRE mice exhibited hyperactive behavior combined with attention-deficit, sleep disturbance and impulsivity that affect their learning and memorization performances. These mice may therefore serve as a model to study attention deficit / hyperactivity disorder. Our work also pointed out the need for proper behavioral analysis of control groups in transgenic animal generation to avoid misinterpretation and misattribution of behavioral traits.

animal behavior and cognition↗