UC San Diego

Osteoarthritis (OA) is the most common joint disorder, and obesity is a risk factor for OA development. However, how metabolic alterations associated with obesity contributing to OA is unclear. Because dysregulation of adenosine monophosphate-activated protein kinase (AMPK), a master regulator of energy balance, has been linked to both obesity and OA, we investigate the role of AMPK in obesity-induced OA. To do so, we subjected mice with knockout (KO) of AMPKα1, the predominant catalytic subunit of AMPK, and wild type (WT) control mice at 3 months of age to a long-term (40 weeks) high-fat diet (HFD) and control diet (CD). We then assessed metabolic changes and cartilage degeneration that is a hallmark of OA. We found that AMPKα1 KO compared to WT mice after a long-term HFD displayed profound metabolic alterations such as substantial increase in body weight, fasting blood glucose levels and severe glucose intolerance. These were likely attributed to that AMPKα1 KO mice had reduced ability of producing insulin and development of leptin resistance in response to HFD, supported by significantly lower plasma levels of insulin and leptin. AMPKα1 KO compared to WT mice after HFD also exhibited systemic inflammation, evidenced by marked induction of plasma levels of TNFα, an inflammatory marker. Importantly, AMPKα1 KO compared to WT mice after HFD presented OA pathology, because mild but significant cartilage degeneration were observed. Taken together, these results suggest that dysregulation of AMPK could contribute to OA development associated with obesity.