Sexually dimorphic effects of angiopoietin-like 2 on energy metabolism and hypothalamic neuropeptide regulation.

Background: Adipokines regulate body weight and metabolism by targeting the hypothalamus, influencing feeding, energy expenditure (EE) and insulin sensitivity. Angiopoietin-like 2 (Angptl2) is a pro-inflammatory adipokine linking obesity to insulin resistance. Both Angptl2 and its receptor are expressed in the central nervous system. Yet, the contribution of Angptl2 to the regulation of energy metabolism and relevant hypothalamic neuropeptides in male and female mice is unknown. We aim at determining the impact of Angptl2 knockdown (KD) on energy balance, nutrient partitioning and hypothalamic responses to a standard (STD) or high-fat diet (HFD) in mice.

Methods: Three-month-old male and female Angptl2-KD mice and wildtype (WT) littermates were fed 16 weeks either a STD or a HFD. Body weight, food consumption and insulin sensitivity were assessed along with measurements of EE, respiratory exchange ratio (RER) and locomotor activity. We quantified the expression of Angptl2 and its receptors itga5, mag and pirb in the medio-basal hypothalamus (MBH) of WT mice, and MBH neuropeptide Y (NPY), agouti-related neuropeptide (AgRP) and proopiomelanocortin (POMC) gene expression in both KD and control fasting mice.

Results: Lack of Angptl2 reduced food intake in males on both diets, and in females on HFD. In KD males, this anorexigenic effect was associated with lower body weight, increased EE, improved insulin sensitivity and lower hypothalamic orexigenic NPY expression compared to controls. Female Angptl2-KD mice however, exhibited unaltered body weight, EE and insulin sensitivity, and elevated NPY, AgRP and MC4R expression compared to controls. Fasting caused an increase in the MBH of mag expression in males and females but Angptl2 expression only in female mice.

Conclusions: Angptl2 KD improved diet-induced obesity and associated metabolic dysfunction in male mice. The lack of similar changes in female mice and divergent MBH neuropeptide profile suggest that sex-dependent mechanisms underly the anabolic effects of this proinflammatory adipokine.