Endogenous expression of cellular communication network factor 5 on normal β-cells growth and insulin resistance caused by diet-induced obesity

Cellular communication network factor 5 (CCN5; WISP2) is a matricellular protein. Our previous studies suggest that CCN5 promotes the proliferation and survival of pancreatic β-cells, thereby conferring metabolic advantages. A recent report indicated that a systemic deficiency in CCN5 expression leads to increased adiposity, glycemia, and insulin resistance. These conditions worsen when subjected to a high-fat diet (HFD). To further understand the metabolic roles of endogenous CCN5, we reassessed CCN5 knockout mice that were fed either a chow diet or a 60% HFD. In contrast to the previous report, our findings reveal that CCN5 knockout mice of both sexes maintain normal lean/fat mass, body weight, glycemia, insulin levels, and insulin sensitivity when fed a chow diet. However, the expression of the CCN5 gene seems to be essential for maintaining normal β-cell growth. Even under the stress of extended HFD feeding, CCN5 knockout mice exhibited similar weight gain and did not show an elevation in glycemia. Male knockout mice displayed improved glucose tolerance, insulin sensitivity, and a slight decrease in glycemia compared with wild-type counterparts. Interestingly, the lack of CCN5 did not affect obesity-induced β-cell compensation. These findings further reinforce the role of CCN5 as a comprehensive metabolic regulator, although the effects could be sex specific. In male mice affected by diet-induced obesity, the endogenous expression of CCN5 seems to have a negative impact on insulin and glucose tolerance. Under different physiological conditions, the systemic effects of CCN5 and its specific influence on β-cells may interact to shape the metabolic outcomes.<b>NEW & NOTEWORTHY</b> This study challenges prior findings by demonstrating that CCN5 knockout mice maintain normal body weight and glucose tolerance on a chow diet but exhibit impaired β-cell expansion. Strikingly, under a high-fat diet, male knockout mice display enhanced glucose tolerance without compromising β-cell compensation. These results suggest that CCN5's influence on metabolism is context-dependent, shaped by both diet and sex, and may critically modulate metabolic outcomes through its regulatory effects on β-cells.