Abstract
BackgroundGrowing evidence supports the role of gut microbiota in obesity and its related disorders including type 2 diabetes. Ob/ob mice, which are hyperphagic due to leptin deficiency, are commonly used models of obesity and were instrumental in suggesting links between gut microbiota and obesity. Specific changes in their gut microbiota such as decreased microbial diversity and increased Firmicutes to Bacteroidetes ratio have been suggested to contribute to obesity via increased microbiota capacity to harvest energy. However, the differential development of ob/ob mouse gut microbiota compared to wild type microbiota and the role of hyperphagia in their metabolic impairment have not been investigated thoroughly.ResultsWe performed a 10-week long study in ob/ob (n = 12) and wild type control (n = 12) mice fed ad libitum. To differentiate effects of leptin deficiency from hyperphagia, we pair-fed an additional group of ob/ob mice (n = 11) based on the food consumption of control mice. Compared to control mice, ob/ob mice fed ad libitum exhibited compromised glucose metabolism and increased body fat percentage. Pair-fed ob/ob mice exhibited even more compromised glucose metabolism and maintained strikingly similar high body fat percentage at the cost of lean body mass. Acclimatization of the microbiota to our facility took up to 5 weeks. Leptin deficiency impacted gut microbial composition, explaining 18.3% of the variance. Pair-feeding also altered several taxa, although the overall community composition at the end of the study was not significantly different. We found 24 microbial taxa associations with leptin deficiency, notably enrichment of members of Lactobacillus and depletion of Akkermansia muciniphila. Microbial metabolic functions related to energy harvest, including glycan degradation, phosphotransferase systems and ABC transporters, were enriched in the ob/ob mice. Taxa previously reported as relevant for obesity were associated with body weight, including Oscillibacter and Alistipes (both negatively correlated) and Prevotella (positively correlated).ConclusionsLeptin deficiency caused major changes in the mouse gut microbiota composition. Several microbial taxa were associated with body composition. Pair-fed mice maintained a pre-set high proportion of body fat despite reduced calorie intake, and exhibited more compromised glucose metabolism, with major implications for treatment options for genetically obese individuals.
Highlights
Growing evidence supports the role of gut microbiota in obesity and its related disorders including type 2 diabetes
To further investigate whether the differences are due to leptin deficiency or hyperphagia, we studied a third group of ob/ob mice that was pair-fed based on the food consumption of the wild type mice (OB-PF)
Despite a slow recovery in the following weeks, ob mice pair-fed according to wild type controls (WT) intake (OB-PF) mice had a net loss in lean body mass over the study period, while OB and WT mice had a net gain in lean body mass (Fig. 1h)
Summary
Growing evidence supports the role of gut microbiota in obesity and its related disorders including type 2 diabetes. Studies on the leptin-deficient (ob/ob) mouse model for obesity have shown that, compared to normal wild type mice, ob/ob mice have markedly different gut microbial composition and increased capacity to harvest energy from food [8]. Colonization of germ-free wild type mice with ob/ob mouse microbiota led to a significantly greater increase of adiposity compared to colonization from lean mouse microbiota [8], hinting that this increased capacity may be transmissible. These results suggest that there is a bidirectional host-microbial cross-talk where the host selects the microbiota depending on its genotype/phenotype (e.g., leptin deficiency), and the microbiota influences the host phenotype (e.g., adiposity). We still do not know how the host and the gut microbiota shape each other over time in ob/ob mice, and how this process differs from wild type mice
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