Role of Kallikrein 7 in Body Weight and Fat Mass Regulation

Abstract

Increased plasma and adipose tissue protease activity is observed in patients with type 2 diabetes and obesity. It has been proposed that specific proteases contribute to the link between obesity, adipose tissue inflammation and metabolic diseases. We have recently shown that ablation of the serine protease kallikrein-related peptidase 7 (Klk7) specifically in adipose tissue preserves systemic insulin sensitivity and protects mice from obesity-related AT inflammation. Here, we investigated whether whole body Klk7 knockout (Klk7−/−) mice develop a phenotype distinct from that caused by reduced Klk7 expression in adipose tissue. Compared to littermate controls, Klk7−/− mice gain less body weight and fat mass both under chow and high fat diet (HFD) feeding, are hyper-responsive to exogenous insulin and exhibit preserved adipose tissue function due to adipocyte hyperplasia and lower inflammation. Klk7−/− mice exhibit increased adipose tissue thermogenesis, which is not related to altered thyroid function. These data strengthen our recently proposed role of Klk7 in the regulation of body weight, energy metabolism, and obesity-associated adipose tissue dysfunction. The protective effects of Klk7 deficiency in obesity are likely linked to a significant limitation of adipocyte hypertrophy. In conclusion, our data indicate potential application of specific KLK7 inhibitors to regulate KLK7 activity in the development of obesity and counteract obesity-associated inflammation and metabolic diseases.

Overexpressing high levels of human vaspin limits high fat diet-induced obesity and enhances energy expenditure in a transgenic mouse

“…Knockout of KLK7 in AT dampened obesity-induced AT inflammation and preserved insulin sensitivity in mice ( 14 ). Also, a whole-body knockout of KLK7 improved diet-induced metabolic alterations with more pronounced reduction of diet-induced weight gain ( 15 ). Anti-inflammatory effects of vaspin in the liver have been in part ascribed to vaspins’ interaction with the ER chaperon GRP78 on the cell surface of hepatocytes ( 10 ).…”

Identification of novel key molecular signatures in the pathogenesis of experimental diabetic retinopathy

“…34 Moreover, it has been found to catalyze insulin degradation in vitro, and its ablation protects mice from high-fat-induced adipose tissue inflammation and improves systemic insulin sensitivity. 35,36 Our analysis showed a decline in Klk7 expression throughout the course of diabetes, which may be a protective response to insulin deficiency. Similarly, expression of the KLK7 inhibitor, Vaspin, was induced in obesity and type 2 diabetes.…”

Integrated transcriptome analysis reveals roles of long non-coding RNAs (lncRNAs) in caprine skeletal muscle mass and meat quality

“…For example, up-regulated MSTRG.12645.1 in Longissimus dorsi muscle of LC goats compared to ZB goats would be co-expressed with KLK7, which was also identi ed as an up-regulated gene in LC goats (Supplementary File 3). KLK7 led to an increase of body fat mass in mice [31]. The up-regulated XR_001918823.1 in LC goats would target SLC7A8 that was up-regulated in Longissimus dorsi muscle of LC goats compared to ZB goats (Supplementary File 3).…”

“…For example, the target genes CDK1, GREM1, MEGF10, and DNER were involved in muscle cell differentiation process (Supplementary File 5). The target genes RORC, KLK7 and RYR3 were relate to adipogenesis [29][30][31], while the target genes GREM1 and LOXL2 were involved in connective tissue development process affecting meat tenderness [32].…”