Metabolic Abnormalities and Adipose Tissue Leukocyte Dynamics in a Murine Model of Obesity, Weight Loss, and Weight Regain

Abstract

Obesity is associated with pro-inflammatory changes within adipose tissue which are mechanistically linked to the development of cardiometabolic disease. Currently, little is known regarding whether weight loss resolves obesity-induced changes including adipose tissue inflammation. We sought to clarify unresolved mechanisms that control adipose tissue leukocyte dynamics and metabolic dysfunction during obesity, weight loss, and weight regain. We first identified CD64 as a better marker than what has been previously used for identifying adipose tissue macrophages in mice. Use of this marker allows the definitive identification of macrophages from dendritic cells within adipose tissue and resolves controversies in the field regarding this population. Obesity was induced using a high-fat diet (60% kcal derived from fat) for 12 weeks and weight loss was achieved by switching animals back to normal diet (13.5% kcal derived from fat) for an additional 8-24 weeks. We show that even a prolonged six-month weight loss cycle in mice fails to completely resolve obesity-induced adipose tissue macrophage activation which may contribute to the persistent adipose tissue damage and reduced insulin sensitivity observed in formerly obese mice. Finally, we investigated if unique metabolic abnormalities develop in formerly obese mice upon HFD re-challenge for an additional 6 weeks. Weight regain was associated with impaired adipose tissue expansion, hyperinsulinemia, hepatic steatosis and elevated serum transaminase concentrations. We conclude that obesity imparts a lasting impact on adipose tissue immune and metabolic function that persists despite weight loss and may have long-term negative effects on health. As a result, weight regain in formerly obese mice is accompanied by hastened development of potentially severe metabolic abnormalities.