ObjectivesThe p62 deficient mouse exhibits a similar but unique phenotype of obesity compared to other diet‐induced or genetically modified obesity models. Our study aimed to further characterize physical and metabolic properties of p62 knockout mice.MethodsMale C57BL/6 p62 knockout (p62−/−, 14 weeks old, n=9) and sex‐/age‐matched C57BL/6 wildtype control mice (CON, n=9) were studied. All mice were raised separately with access to standard rodent chow and water ad libitum. Food intake and body weight changes were monitored biweekly for 20 weeks. At 24 and 34 weeks of age, all mice went through in vivo assessments of body composition (dual X‐ray absorptiometry), neuromuscular function (grip strength and inclined plane test), and oral glucose tolerance tests (OGTT). Additionally, at 34 weeks of age, hindlimb muscles (i.e., gastrocnemius, soleus, and plantaris) and the spleen were extracted and weighed. The isolated muscles were analyzed for myofiber cross‐sectional area (CSA) and expression levels of regulatory proteins for muscle growth (i.e., mTOR, AKT, atrogin1, and MuRF1), insulin signaling [i.e., insulin receptor β (IR‐β) and GLUT4], and proinflammation (i.e., TNF‐α).Resultsp62−/− demonstrated greater daily food intake and weight gain leading to obesity at 22 weeks of age compared to CON (p<0.05). At 24 weeks of age, p62−/− displayed greater total body mass and fat mass (p<0.05), and these changes were even greater at 34 weeks of age. p62−/− showed higher fasting blood glucose levels and diminished blood glucose clearance leading to greater postprandial blood glucose (p<0.05). No significant differences in grip strength and sensorimotor function were observed in p62−/− compared to CON. In vitro analysis revealed no group difference in muscle wet weights; however, spleen weights were greater in p62−/− than CON. p62−/− exhibited greater myofiber CSA than CON (p<0.05). There was a suppressed expression ratio of phosphorylated AKT to total AKT in the gastrocnemius of p62−/− (p<0.05).ConclusionYoung adult p62−/− mice developed obesity accompanied by insulin resistance and systemic inflammation, which was attributable, at least in part, to increased food intake. However, it is noteworthy that p62−/− mice exhibited greater myofiber CSA while maintaining skeletal muscle mass and function during progression of obesity.Support or Funding InformationJiwon Co. LtdThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.