Hjem
Klinisk institutt 2

Midtveisevaluering - Divya Sri Priyanka Tallapragada

Hovedinnhold

 

ABSTRAKT

Adipose tissue helps in the maintenance of systemic energy balance by modulating energy intake and energy expenditure. Obesity i.e., an excessive increase in white adipose tissue mass is a global public health concern. Obesity significantly shortens life expectancy and is a major driving factor in the development of cardio-metabolic diseases such as type 2 diabetes (T2D), stroke, hypertension as well as non-metabolic comorbidities such as depression, Alzheimer’s disease and many forms of cancer. Increased intrabdominal adiposity/omental (OM) adiposity increases risk of metabolic diseases whereas subcutaneous (SC)  adiposity exerts little or no risk.

Genome wide association studies have identified several genetic susceptibility variants associated with anthropometric traits of obesity and regional fat distribution. However, most of these variants lie in the non-coding regions of genome limiting the  translational ability  of these discoveries. In  obesity, many  of the variants are likely to affect cellular processes in adipose tissue. A better understanding of how genetic variants affect adipose tissue can ultimately allow us to translate our research to provide better prediction and treatment options to tackle  obesity.

The goal of this project is to explore the role of adipose tissue heterogeneity and establish and apply novel adipocyte culture models and methods for studying causal mechanisms underlying genetic variants that associate with visceral adiposity. We identified differentially expressed (DE) genes in whole adipose tissue, mature adipocytes and stromal vascular fraction (SVF) from SC and OM depots, and from whole adipose tissue from SC and OM depots exposed to stress conditions. We overlapped DE genes from these analyses to identify key genes involved in adipocyte metabolism. We identified phosphatidylethanolamine N- methyltransferase (PEMT) as an interesting candidate gene highly expressed in SC depot which plays a key role in the maintenance of membrane integrity and energy   metabolism.

To further explore different candidate genes and role of genetic variants, we standardized differentiation protocol to promote differentiation of adipocyte precursor cells derived from OM depot and established immortalized SC and OM adipocyte precursor lines. We are currently characterizing these lines using RNA- sequencing and functional assays assessing glucose and lipid metabolism, mitochondrial respiratory capacity and oxidative stress. Solute Carrier Family 7 Member 10 (SLC7A10) is a neutral amino transporter highly expressed in the OM depot and inversely associated with central obesity, adipocyte size and insulin resistance. Using the immortalized lines, we are now characterizing the role of SLC7A10 in different adipose depots. Furthermore, we are going to use a novel post-clonal variant editing approach, CRISPR- SAVE (Clustered Regularly Interspaced Short Palindromic Repeats -Scalable Accurate Variant Editing) to investigate role of genetic variants from a visceral mass associated risk   locus.

Together, these data will help in developing tools and methods to find causal gene(s) and variant(s) in each locus and, identify the altered molecular mechanisms and physiological pathways leading to altered  cellular functions in adipose  tissue.