Defining the Role of HSD17B12 in Body Adiposity Regulation
Aims:
This study proposes that inhibiting the enzymatic activity of HSD17B enzymes could be utilized as a novel approach to control body weight, liver function, and adiposity. Hence the aims of this research project are (i) To analyse HSD17B12 expression and lipid droplet formation in various mouse organs during fasting, re-feeding, during obesity insult, and in mouse models; (ii) To analyze the putative prevention of weight gain by deletion these genes in mice with high-fat diet models; and (iii) To facilitate the generation of specific inhibitors for HSD17B12-enzyme using modeling methods, and to test the efficacy of these inhibitors in vitro and in mouse models in vivo.
Research materials and methods:
As research models, we primarily use wild-type and genetically modified mice and in vitro cell systems. The mice will be placed on a chow diet and challenged with a high-fat diet (HFD; 40 kcal% fat) or with a high-fat-choline-deficient diet (60 kcal% fat) that induces drastic weight gain, liver steatosis, and fibrosis in wild-type mice. Based on previous data, 12-week-long dietary interventions will be used. Primary endpoints include metabolomics, imaging of hepatocytes, measurement of fat and bile acids, steroid profiling, and RNAseq analysis.
The known HSD17B12 inhibitor (INH-12) will be tested for its stability, half-life, and toxicity in cell lines in vitro and in mice in vivo. If the mouse enzyme is inhibited by INH-12, the ability of the inhibitor to prevent the weight gain in mice with HFD diet will be tested as a proof-of-principle. By these tests, I am aiming to define whether pharmacological inhibition replicates the weight loss seen in genetic ablation. In addition, novel small-molecule HSD17B12 inhibitors will be produced and tested to select hit compounds for further analysis. Therefore, the proposed project activity seeks to explore the role of HSD17B12 inhibitors in body adiposity regulation, and to analyse the effect of inhibiting the enzyme in liver function and metabolic-related diseases, with the ultimate goal of translating these findings into better clinical care of the obesity epidemic.
Key words:
HSD17B12, adiposity regulation, inhibitors, drug discovery, metabolic dysfunction
Matti Poutanen
Professor
Assessment of Metabolic Health and Flexibility Across the Liver-Heart-Adipose Tissue Axis in Aging Populations with Obesity and Diabetes
The project aims to address critical gaps in understanding metabolic health and its challenges across these interlinked organs in vulnerable populations.
Metabolic health is essential for overall well-being, but obesity and diabetes bidirectionally with aging disrupt this balance, leading to systemic consequences such as cardiovascular and hepatic diseases. The liver, heart, and adipose tissues play a central role in regulating energy metabolism, and its dysfunction — manifesting as ectopic fat deposition, dyslipidemia, insulin resistance, and chronic inflammation — drives many diseases’ progression. This research proposal seeks to elucidate the metabolic interplay between the liver, heart, and adipose tissues (including white and brown) via assessing metabolic health and flexibility. Advances in positron emission tomography (PET) and metabolic tracers, particularly radiolabeled substrates, now enable precise in vivo assessments of organ-specific metabolic flexibility and dysfunction, providing an opportunity to understand these complex interactions better. Previous results of longitudinal preclinical studies using models of obesity, type 2 diabetes, and structural and functional abnormalities of the heart muscle demonstrated a metabolic shift in liver and heart metabolism as with the stage of the disease but also in healthy conditions with aging. That observation, combined with human imaging and employing advanced PET quantification techniques, can open new findings to our understanding of the complex metabolic process in the body. The non-invasive nature of PET allows for quantification of substrate utilization, leading subsequently to the assessment of organ cross-talk and metabolic flexibility, paving the way for novel biomarkers and early prediction tools. By leveraging cutting-edge tools such as [18F]FDG and [18F]FTHA-PET, the establishment of F-radiolabeled lactate ([18F]FLac) and de novo VLDL production studies, this organ-axis approach aims to redefine the evaluation of metabolic health, offering meaningful benefits to aging populations affected by obesity and diabetes.