Head: Agnieszka Dobrzyń
Sai Santosh Babu Komakula,
Our research group carries out cutting edge, multidisciplinary studies on signalling and transcriptional cascades that have far-reaching implications on lipid metabolism and human metabolic diseases, i.e. diabetes and obesity-related heart dysfunctions. A long-term goal of our research is to gain in-depth understanding of the functional interaction between transcription factors and obesity related disorders. A high priority is to understand the role of lipid metabolites in the development of lipid-induced insulin resistance and beta-cell dysfunction. A second priority is to gain insights into the functional role of stearoyl-CoA desaturase (SCD) for heart, skeletal muscle and pancreatic islet metabolism regulation, because this will increase our understanding of how lipid partitioning is controlled and may have important implications for the pathogenesis of the Metabolic Syndrome.
Studies in our lab are characterized by a powerful combination of careful biochemistry, whole animal nutrition, molecular genetics and mouse genetics putting our laboratory in the vanguard of those exploring lipid homeostasis and providing essential insight into the causes of many serious diseases that can result when metabolic homeostasis fails.
We identified several important new regulators of cell metabolism. We have shown that SCD1 deficiency causes a shift in cardiac substrate utilization from fatty acids (FA) to glucose by upregulating insulin signaling, decreasing FA availability, and reducing expression of FA oxidation genes in the heart (Dobrzyn et al., Am J Physiol 2008). This increase in cardiac insulin sensitivity and glucose utilization due to SCD1 deficiency could prove therapeutic in pathological conditions such as obesity that are characterized by skewed cardiac substrate utilization. We tested this hypothesis using obese leptin-deficient ob/ob mouse model.
We showed that disruption of SCD1 gene improves cardiac function in ob/ob mice by correcting systolic and diastolic dysfunction without affecting levels of plasma triglycerides and FA. The improvement was associated with reduced expression of genes involved in FA transport and lipid synthesis in the heart, as well as reduction in cardiac free FA, diacylglycerol, TG and ceramide levels. Moreover, SCD1 deficiency reduced cardiac apoptosis in ob/ob mice due to increased expression of antiapoptotic factor Bcl-2 and inhibition of inducible nitric oxide synthase and caspase-3 activities. Reduction in myocardial lipid accumulation and inhibition of apoptosis appear to be one of the main mechanisms responsible for improved left ventricle function in ob/ob mice caused by SCD1 deficiency (Dobrzyn et al. JLR in press).
In a similar fashion, we study the basis for increased insulin sensitivity, which led us to find that SCD1 deficiency activates the insulin signaling pathway and thus, GLUT4 membrane translocation. SCD1 deficiency increases whole body insulin sensitivity and glucose tolerance in insulin resistant muscles.
Figure 1. The effect of SCD1 deficiency on insulin signaling - proposed mechanism. In the absence of SCD1, the expression of fatty acid oxidation genes, the activity of AMPK pathway and the rate of b-oxidation are significantly increased which, together with reduced lipogenesis, leads to a decrease in the intracellular accumulation of lipids. The reduction of the lipid content disinhibits Akt and IRSs. Also, the expression and activity of PTP-1B are decreased leading to an increase in phosphorylation of IR and IRS 1 and -2. These phenomena, together with the consequent activation of Akt kinase lead to increased GLUT4 membrane translocation and enhanced glucose transport. (Dobrzyn et al. Biochim Biophys Acta - Bioenerg, 2010)
Figure 2. Endocannabinoids induce stress fiber formation in pancreatic beta cells. F-actin (phalloidin-Alexa 488) and myosin IIB (Cy3) in control (A) and anandamide stimulated (B) INS-1E cells.
- Malenczyk K, Jazurek M, Keimpema E, Silvestri C, Janikiewicz J, Mackie K, Di Marzo V, Redowicz MJ, Harkany T, Dobrzyn A: CB1 cannabinoid receptors couple to focal adhesion kinase to control insulin release. J Biol Chem. 2013, 288(45): 32685-32699.
- Dobrzyn P, Pyrkowska A, Duda MK, Bednarski T, Maczewski M, Langfort J, Dobrzyn A: Expression of lipogenic genes is upregulated in the heart with exercise-training induced but not pressure overload-induced left ventricular hypertrophy. Am J Physiol Endocrinol Metab 2013, 304(12): E1348-1358.
- Dziewulska A, Dobrzyn P, Jazurek M, Pyrkowska A, Ntambi JM, Dobrzyn A: Monounsaturated fatty acids are required for membrane translocation of protein kinaase C-theta induced bylipid overload in skeletal muscle. Mol Membr Biol 2012, 29(7):309-320.
- Dobrzyn P, Dobrzyn A, Miyazaki M, Ntambi JM: Loss of stearoyl-CoA desaturase 1 rescues cardiac function in obese leptin-deficient mice. J Lipid Res. 2010; 51: 2202-2210.
- Dobrzyn P, Jazurek M, Dobrzyn A: Stearoyl-CoA desaturase and insulin resistance - What is the molecular switch. Biochim Biophys Acta - Bioenerg. 2010; 1797: 1189-1194.