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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.
Highlights
As multiple kallikrein proteases including KLK7 are expressed in thyroid tissue [37], we investigated potential effects of Klk7 deficiency on thyroid hormone generation, circulating thyroid stimulating hormone (TSH), total T4 (TT4), and free T3 concentrations
We focused on the impact of Klk7 deletion in AT on proteome composition in ATKlk7−/− mice
In the constitutional knockout, the protective effects of Klk7 deficiency against obesity-associated adipose dysfunction and subsequently insulin resistance under high fat diet (HFD) can be mainly attributed to lower fat mass
Summary
Elevated plasma and AT protease activity is associated with obesity, type 2 diabetes and chronic inflammation [4,5]. Intra- and extracellular proteases are significantly contributing to AT function, and dysregulation of proteolytic activities represents a direct link between obesity, AT inflammation and cardio-metabolic diseases. Global or conditional knock out of proteases or modulation of specific proteases’ activity reduced weight gain, inflammation and improved metabolic parameters under high fat diet (HFD) [5,6,7,8]. Overexpression of endogenous serpin inhibitors such as α1-antitrypsin (SERPINA1) and vaspin (SERPINA12) in AT reduces weight gain, inflammation and preserves insulin sensitivity under high fat diet [6,9]
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