ObjectiveGut microbiota may promote positive energy balance; however, germfree mice can be either resistant or susceptible to diet-induced obesity (DIO) depending on the type of dietary intervention. We here sought to identify the dietary constituents that determine the susceptibility to body fat accretion in germfree (GF) mice.MethodsGF and specific pathogen free (SPF) male C57BL/6N mice were fed high-fat diets either based on lard or palm oil for 4 wks. Mice were metabolically characterized at the end of the feeding trial. FT-ICR-MS and UPLC-TOF-MS were used for cecal as well as hepatic metabolite profiling and cecal bile acids quantification, respectively. Hepatic gene expression was examined by qRT-PCR and cecal gut microbiota of SPF mice was analyzed by high-throughput 16S rRNA gene sequencing.ResultsGF mice, but not SPF mice, were completely DIO resistant when fed a cholesterol-rich lard-based high-fat diet, whereas on a cholesterol-free palm oil-based high-fat diet, DIO was independent of gut microbiota. In GF lard-fed mice, DIO resistance was conveyed by increased energy expenditure, preferential carbohydrate oxidation, and increased fecal fat and energy excretion. Cecal metabolite profiling revealed a shift in bile acid and steroid metabolites in these lean mice, with a significant rise in 17β-estradiol, which is known to stimulate energy expenditure and interfere with bile acid metabolism. Decreased cecal bile acid levels were associated with decreased hepatic expression of genes involved in bile acid synthesis. These metabolic adaptations were largely attenuated in GF mice fed the palm-oil based high-fat diet. We propose that an interaction of gut microbiota and cholesterol metabolism is essential for fat accretion in normal SPF mice fed cholesterol-rich lard as the main dietary fat source. This is supported by a positive correlation between bile acid levels and specific bacteria of the order Clostridiales (phylum Firmicutes) as a characteristic feature of normal SPF mice fed lard.ConclusionsIn conclusion, our study identified dietary cholesterol as a candidate ingredient affecting the crosstalk between gut microbiota and host metabolism.

Peri-conceptional exposure to maternal obesogenic nutrition is associated with in utero programming of later-life overweight and metabolic disease in the offspring. We aimed to investigate whether dietary intervention with a modified fatty acid quality in an obesogenic high-calorie (HC) diet during the preconception and gestational phases can improve unfavourable effects of an adipogenic maternal environment. In NMRI mice, peri-conceptional and gestational obesity was induced by feeding a HC diet (controls), and they were compared with dams on a fat-modified (Fat-mod) HC diet of the same energy content but enriched with medium-chain fatty acids (MCFAs) and adjusted to a decreased ratio of n-6 to n-3 long-chain polyunsaturated fatty acids (LC-PUFAs). Effects on maternal and placental outcomes at delivery (day 17.5 post coitum) were investigated. Despite comparable energy assimilation between the two groups of dams, the altered fatty acid composition of the Fat-mod HC diet induced lower maternal body weight, weights of fat depots, adipocyte size, and hepatic fat accumulation compared to the unmodified HC diet group. Further, there was a trend towards lower fasting glucose, insulin and leptin concentrations in dams fed the Fat-mod HC diet. Phenotypic changes were accompanied by inhibition of transcript and protein expression of genes involved in hepatic de novo lipogenesis comprising PPARG2 and its target genes Fasn, Acaca, and Fabp4, whereas regulation of other lipogenic factors (Srebf1, Nr1h3, Abca1) appeared to be more complex. The modified diet led to a sex-specific placental response by upregulating PPARG-dependent fatty acid transport gene expression in female versus male placentae. Qualitative modification of the fatty acid spectrum of a high-energy maternal diet, using a combination of both MCFAs and n-3 LC-PUFAs, seems to be a promising interventional approach to ameliorate the adipogenic milieu of mice before and during gestation.

Although adaptive servo-ventilation (ASV) effectively supresses central sleep apnoea (CSA), little is known about real-world indications of ASV therapy, and its effects on quality of life (QoL). This report details the design, baseline characteristics, indications for ASV and symptom burden in patients enrolled in the Registry on the Treatment of Central and Complex Sleep-Disordered Breathing with Adaptive Servo-Ventilation (READ-ASV). This multicentre, European, non-interventional trial enrolled participants prescribed ASV in clinical practice between September 2017 and March 2021. An expert review board assigned participants to ASV indications using a guideline-based semi-automated algorithm. The primary endpoint is change in disease-specific QoL (based on the Functional Outcomes of Sleep Questionnaire [FOSQ]) from baseline to 12-month follow-up. The registry population includes 801 participants (age 67±12 years, 14% female). Indications for ASV were treatment-emergent or persistent CSA (TE-CSA; 56%), CSA in cardiovascular disease (31%), unclassified CSA (2%), coexisting obstructive sleep apnoea (OSA) and CSA (OSA-CSA; 4%), OSA (3%), CSA in stroke (2%), and opioid-induced CSA (1%). Baseline mean apnoea-hypopnoea index was 48±23/h (≥30/h in 78%), FOSQ score was 16.7±3.0 (<17.9 in 54%) and Epworth Sleepiness Scale (ESS) score was 8.8±4.9 (>10 in 34%); 62% of patients were symptomatic (FOSQ score <17.9 or ESS score >10). In summary, the most common indications for ASV were TE-CSA or CSA in cardiovascular disease (excluding systolic heart failure). Patients using ASV in clinical practice had severe SDB and were often symptomatic. One-year follow-up will provide data on the effects of ASV on QoL, respiratory parameters and clinical outcomes in these patients.