A novel fatty acid mimetic with pan-PPAR partial agonist activity inhibits diet-induced obesity and metabolic dysfunction-associated steatotic liver disease.

OBJECTIVE: The prevalence of metabolic diseases is increasing globally at an alarming rate; thus, it is essential that effective, accessible, low-cost therapeutics are developed. Peroxisome proliferator-activated receptors (PPARs) are transcription factors that tightly regulate glucose homeostasis and lipid metabolism and are important drug targets for the treatment of type 2 diabetes and dyslipidemia. We previously identified LDT409, a fatty acid-like compound derived from cashew nut shell liquid, as a novel pan-active PPARα/γ/δ compound. Herein, we aimed to assess the efficacy of LDT409 in vivo and investigate the molecular mechanisms governing the actions of the fatty acid mimetic LDT409 in diet-induced obese mice. METHODS: C57Bl/6 mice (6-11-month-old) were fed a chow or high fat diet (HFD) for 4 weeks; mice thereafter received once daily intraperitoneal injections of vehicle, 10 mg/kg Rosiglitazone, 40 mg/kg WY14643, or 40 mg/kg LDT409 for 18 days while continuing the HFD. During treatments, body weight, food intake, glucose and insulin tolerance, energy expenditure, and intestinal lipid absorption were measured. On day 18 of treatment, tissues and plasma were collected for histological, molecular, and biochemical analysis. RESULTS: We found that treatment with LDT409 was effective at reversing HFD-induced obesity and associated metabolic abnormalities in mice. LDT409 lowered food intake and hyperlipidemia, while improving insulin tolerance. Despite being a substrate of both PPARα and PPARγ, LDT409 was crucial for promoting hepatic fatty acid oxidation and reducing hepatic steatosis in HFD-fed mice. We also highlighted a role for LDT409 in white and brown adipocytes in vitro and in vivo where it decreased fat accumulation, increased lipolysis, induced browning of WAT, and upregulated thermogenic gene Ucp1. Remarkably, LDT409 reversed HFD-induced weight gain back to chow-fed control levels. We determined that the LDT409-induced weight-loss was associated with a combination of increased energy expenditure (detectable before weight loss was apparent), decreased food intake, increased systemic fat utilization, and increased fecal lipid excretion in HFD-fed mice. CONCLUSIONS: Collectively, LDT409 represents a fatty acid mimetic that generates a uniquely favorable metabolic response for the treatment of multiple abnormalities including obesity, dyslipidemia, metabolic dysfunction-associated steatotic liver disease, and diabetes. LDT409 is derived from a highly abundant natural product-based starting material and its development could be pursued as a therapeutic solution to the global metabolic health crisis.

Strain specific differences in rates of Photosystem II repair in picocyanobacteria correlate to differences in FtsH protein levels and isoform expression patterns.

Picocyanobacteria are the numerically dominant photoautotrophs of the oligotrophic regions of Earth's oceans. These organisms are characterized by their small size and highly reduced genomes. Strains partition to different light intensity and nutrient level niches, with differing photosynthetic apparatus stoichiometry, light harvesting machinery and susceptibility to photoinactivation. In this study, we grew three strains of picocyanobacteria: the low light, high nutrient strain Prochlorococcus marinus MIT 9313; the high light, low nutrient Prochlorococcus marinus MED 4; and the high light, high nutrient marine Synechococcus strain WH 8102; under low and high growth light levels. We then performed matched photophysiology, protein and transcript analyses. The strains differ significantly in their rates of Photosystem II repair under high light and in their capacity to remove the PsbA protein as the first step in the Photosystem II repair process. Notably, all strains remove the PsbD subunit at the same rate that they remove PsbA. When grown under low light, MIT 9313 loses active Photosystem II quickly when shifted to high light, but has no measurable capacity to remove PsbA. MED 4 and WH 8102 show less rapid loss of Photosystem II and considerable capacity to remove PsbA. MIT 9313 has less of the FtsH protease thought to be responsible for the removal of PsbA in other cyanobacteria. Furthermore, by transcript analysis the predominant FtsH isoform expressed in MIT 9313 is homologous to the FtsH 4 isoform characterized in the model strain Synechocystis PCC 6803, rather than the FtsH 2 and 3 isoforms thought to be responsible for PsbA degradation. MED 4 on the other hand shows high light inducible expression of the isoforms homologous to FtsH 2 and 3, consistent with its faster rate of PsbA removal. MIT 9313 has adapted to its low light environment by diverting resources away from Photosystem II content and repair.