Researchers identify enzyme in animal model responsible for metabolism disorders due to obesity.


Metabolism experts are increasingly convinced that obesity and many of the pathogenic changes it entails, such as Metabolic Syndrome and type 2 diabetes, are a result of chronic inflammatory processes in fatty (adipose) tissue. Previous studies have shown that the adipose tissue of obese people exhibits higher-than-normal quantities of almost all types of immune and inflammatory cells.  These studies have led the medical community to hypothesize that immune cells play a role in the pathogenic consequences of obesity.  However, little is understood so far about the exact processes that lead to disruptions in metabolism.

Now, a team from the Deutsches Krebsforschungszentrum, (DKFZ) have been able to take a first step towards answering this question by identifying an enzyme in immune cells that is required for metabolically linked pathogenic processes to unfold.  The opensource study is published in the journal Cell Metabolism.

The enzyme, called Kit, is involved in the development of blood and immune cells, as well as stem cells. The current study compared mice that had functioning Kit with animals who had the enzyme turned off in their cells.  When the researchers fed all of the animals a fat-rich diet, the mice with Kit deficiency were protected from obesity and insulin resistance. By contrast, the mice with functioning Kit gained weight and were affected by the associated metabolic disorders.

Previous studies have shown that the Kit enzyme is a member of the large family of receptor tyrosine kinases, for which many highly specific inhibitors have already been developed. Drugs called kinase inhibitors are used to slow down cellular growth in many cancers. Imatinib, for example, is used in the treatment of specific types of leukemia (for example, chronic myeloid leukemia, or CML) and tumours of the gastrointestinal tract with earlier studies reporting a case where type 2 diabetes regressed during treatment with Imatinib.

The team state that apart from its functions in immune cells, Kit also plays a role in many processes that are independent of the immune system. For example, it regulates liver function and impacts the central nervous system and insulin secretion. However, the current study showed that the culprits responsible for obesity and resulting metabolic disorders are immune cells that express Kit, not the effects that are independent of the immune system.

The researchers note that now the key molecule involved in the development of pathogenesis has been identified, however, they still need to find out which of the various immune cell types are actually involved.  The team surmise that the data findings suggest that Kit and Metabolic Syndrome might also be linked in humans.

Source:  The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ)

 

Obesity, insulin resistance, and related pathologies are associated with immune-mediated chronic inflammation. Kit mutant mice are protected from diet-induced obesity and associated co-morbidities, and this phenotype has previously been attributed to their lack of mast cells. We performed a comprehensive metabolic analysis of Kit-dependent KitW/Wv and Kit-independent Cpa3Cre/+ mast-cell-deficient mouse strains, employing diet-induced or genetic (LepOb/Ob background) models of obesity. Our results show that mast cell deficiency, in the absence of Kit mutations, plays no role in the regulation of weight gain or insulin resistance. Moreover, we provide evidence that the metabolic phenotype observed in Kit mutant mice, while independent of mast cells, is immune regulated. Our data underscore the value of definitive mast cell deficiency models to conclusively test the involvement of this enigmatic cell in immune-mediated pathologies and identify Kit as a key hematopoietic factor in the pathogenesis of metabolic syndrome.  Hematopoietic Kit Deficiency, rather than Lack of Mast Cells, Protects Mice from Obesity and Insulin Resistance.   Rodewald et al 2015.

Obesity, insulin resistance, and related pathologies are associated with immune-mediated chronic inflammation. Kit mutant mice are protected from diet-induced obesity and associated co-morbidities, and this phenotype has previously been attributed to their lack of mast cells. We performed a comprehensive metabolic analysis of Kit-dependent KitW/Wv and Kit-independent Cpa3Cre/+ mast-cell-deficient mouse strains, employing diet-induced or genetic (LepOb/Ob background) models of obesity. Our results show that mast cell deficiency, in the absence of Kit mutations, plays no role in the regulation of weight gain or insulin resistance. Moreover, we provide evidence that the metabolic phenotype observed in Kit mutant mice, while independent of mast cells, is immune regulated. Our data underscore the value of definitive mast cell deficiency models to conclusively test the involvement of this enigmatic cell in immune-mediated pathologies and identify Kit as a key hematopoietic factor in the pathogenesis of metabolic syndrome. Hematopoietic Kit Deficiency, rather than Lack of Mast Cells, Protects Mice from Obesity and Insulin Resistance. Rodewald et al 2015.

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