Index: Karolinska Institutet: KI South: Department of Medicine, Huddinge


Altered creatine metabolism in white adipose tissue macrophages promotes adipose tissue dysfunction


Supervisor: Salwan MAQDASY
Department: MEDH
Postal Address: H7/Neo
Hälsovägen 7C (Neo, hiss M1 plan 7)
141 57 Huddinge
SWEDEN
Telephone: 0734486612

E-mail: salwan.maqdasy@ki.se
Homepage: https://medarbetare.ki.se/orgid/5307030205


Besides their capacity to store lipids and secrete hormones, we recently identified white adipocytes to be a “sink” for excess energy storage in the form of phosphocreatine. Obesity is associated with a significant downregulation of creatine kinase B (CKB), an enzyme responsible for the interconversion of ADP and phosphocreatine to ATP and creatine. Alterations in this energy shuttling system result in phosphocreatine accumulation, an increase in ATP/ADP levels, and a “hyperenergetic state” which attenuates AMP-activated protein kinase (AMPK) activity. Collectively, these changes initiate a white adipose tissue (WAT) expansion program characterized by WAT inflammation, a cornerstone in the development of insulin resistance and type 2 diabetes (T2D). However, CKB downregulation alone cannot explain these changes and the mechanisms governing creatine turnover in WAT remain unknown. Creatine is synthesized in a step-wise process from arginine and glycine by the rate limiting enzyme, GATM. As plasma creatine levels remain unaltered during obesity, we hypothesize that phosphocreatine accumulation in WAT is due to local overproduction of creatine. In line with this, Gatm-/- mice are protected against insulin resistance and the metabolic syndrome upon high fat diet (HFD).
We have mapped GATM expression in different resident cells of human WAT. Our analyses demonstrate that GATM is predominantly expressed in adipose tissue macrophages (ATMs). We hypothesize that creatine synthesis in ATMs is up regulated in the obese state. Creatine is taken up by adjacent white adipocytes and trapped in the form of phosphocreatine resulting in WAT inflammation and insulin resistance. To test this hypothesis, we will modulate GATM expression in ATMs and study the effects on WAT inflammation and insulin resistance in vitro. This project will highlight an important inter-cellular mechanism to regulate energy turnover in adipose tissue.

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