["Acta Physiologica, Volume 231, Issue 3, March 2021. ", "\nAbstract\n\nAim\nStudies in the past 15 years have highlighted the role of the gut microbiota in modulation of host metabolism. The observation that germ‐free (GF) mice are leaner than conventionally raised (CONV) mice and their apparent resistance to diet‐induced obesity (DIO), sparked the interest in dissecting the possible causative role of the gut microbiota in obesity and metabolic diseases. However, discordant results among studies leave such relationship elusive.\nIn this study, we compared the effects of chronic Western diet (WD) intake on body weight and metabolic function of GF and CONV mice.\n\n\nMethods\nWe fed GF and CONV mice a WD for 16 weeks and monitored body weight weekly. At the end of the dietary challenge, the metabolic phenotype of the animals was assessed. Muscle carnitine palmitoyltransferase I (CPT1) and liver AMPK activation were investigated.\n\n\nResults\nBoth GF and CONV mice gained weight and developed glucose intolerance when fed a WD. Moreover, WD feeding was associated with increased adipose tissue inflammation, repressed hepatic AMPK activity, fatty liver and elevated hepatic triglycerides in both groups of mice. Enhanced fatty acid oxidation in the GF mouse is one of the proposed mechanisms for their resistance to DIO. The GF mice in this study showed higher CPT1 activity as compared to their CONV counterparts, despite not being protected from obesity.\n\n\nConclusions\nWe provide evidence that the microbiota is not an indispensable factor in the onset of obesity and metabolic dysfunction, suggesting that the relationship between gut bacteria and metabolic diseases needs further exploration.\n\n"]