Molecular Mechanisms Governing the Pharmacology of LDT409 for the Treatment of Metabolic Disease

The prevalence of metabolic diseases, including obesity, dyslipidemia, and type 2 diabetes, is dramatically increasing in the world; thus, it is important to develop effective, low cost, and safe medications to treat these diseases. The peroxisome proliferator-activated receptors (PPARa/g/b) are fatty acid sensors that play important roles in the regulation of lipid metabolism and glucose homeostasis. Herein, we report the characterization of novel compounds derived from phenolic lipids that are abundant in cashew nut shell liquid (CNSL), a by-product of the cashew nut industry. In fact, these compounds retained structural similarity to fatty acids that are known to endogenously activate PPARs. We identified several active phenolic lipid derivatives as single-, dual-, and/or pan-active PPAR agonists, with partial agonist activity and low micromolar potency. Detailed characterization of adipocyte and hepatocyte responses, and in vivo biodistribution studies in zebrafish embryos led to the identification of the lead compound, 23 (LDT409). LDT409 is a novel partial pan-PPAR agonist with potent and balanced affinity for PPARa and PPARg and weak binding affinity to PPARδ (Chapter 2). Moreover, we assessed that chronic treatment with LDT409 was effective at reversing diet-induced obesity and its complications in mice. LDT409 exhibited metabolically beneficial effects on lowering food intake and hyperlipidemia, while improving insulin sensitivity. Surprisingly, LDT409 normalized the HFD-induced weight gain back to chow-fed control mice via targeting these mechanisms: (i) decreasing food intake, (ii) increasing fatty acid utilization, and (iii) decreasing intestinal absorption of fat. We also demonstrated LDT409 ameliorated fatty liver disease and upregulated expression of fasting-associated target genes (e.g., Fgf21, Pdk4), suggesting that LDT409 may mimic fasting to ameliorate fatty liver disease (Chapter 3). Lastly, we explored whether LDT409 induced a “fasting phenotype” to prolong the catabolic state and found that LDT409 yielded a similar response to fasting phenotypically but by RNA-seq LDT409 had sexually dimorphic, wide-ranging effects on signaling pathways that extended beyond fasting- related genes (Chapter 4). In conclusion, LDT409 represents a fatty acid mimic that generates a uniquely favorable metabolic response for the treatment of multiple sequelae of metabolic disease including obesity, dyslipidemia, NAFLD, and type 2 diabetes.

Department dc:contributor.department

Pharmaceutical Sciences

Year dc:date.issued

2023

Author dc:creator

• Sahin, Cigdem

Advisor dc:contributor.advisor

• Cummins, Carolyn

Statement dc:rights

• Attribution-NonCommercial-NoDerivatives 4.0 International

Licence dc:rights.uri

• http://creativecommons.org/licenses/by-nc-nd/4.0/

Handle dc:identifier.uri

https://hdl.handle.net/1807/144531

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/144531