Increased expression of the protein Kallistatin after weight loss induces beneficial metabolic effects: A potential new therapeutic target?

Diabetes, Obesity Metabolism (DOM) NOW—April 2024

Kallistatin, also known as SERPIN A4, is a circulating protein with multiple effects in human body including anti-inflammatory and healing effects. Previous clinical studies in humans have shown that individuals who are overweight or those living with obesity produce less Kallistatin. The role of Kalistatin on glucose and energy metabolism in the setting of insulin resistance and type 2 diabetes as well as its potential as a therapeutic target however is currently unknown.

To investigate this further, mRNA expression of Kallistatin in human subcutaneous white adipose tissue (sWAT) was measured on 47 people before and after weight loss. Participants were derived from the clinical trial ‘Comparison of Low Fat and Low Carbohydrate Diets With Respect to Weight Loss and Metabolic Effects (B-SMART)’. Effects of the protein on transgenic mice that systemically overexpress human Kallistatin and wild type littermate control mice under normal chow and high-fat diet conditions were also studied.

The study showed that the expression of Kallistatin in subcutaneous adipose tissue of people with obesity was increased after diet-induced weight loss. In the mice study, insulin excursions following glucose tolerance, markers of insulin resistance and hyperinsulinemic euglycemic clamp studies confirmed improved insulin sensitivity in mice overexpression the Kallsiatatin gene compared with wild-type mice. Improvement in insulin sensitivity was driven by reduced hepatic insulin resistance, and therefore, provides evidence for direct insulin sensitizing effects of Kallistatin for the first time.

This study suggests that Kallistatin has insulin-sensitizing effects in the liver, and its expression was increased following weight loss. This study provides a good basis to further investigate the function and regulation of this protein as a potential liver-specific target to enhance the beneficial effects of weight loss and potentially inducing long-term diabetes and obesity remission. The study was published in Molecular Metabolism.¹