Inhibition Of acetyl-CoA Carboxylase Research Articles

Enhanced Herbicide Metabolism and Target Site Mutation Enabled the Multiple Resistance to Cyhalofop-butyl, Florpyrauxifen-benzyl, and Penoxsulam in Echinochloa crus-galli.

This study investigated the multiple herbicide resistance (MHR) mechanism of one Echinochloa crus-galli population that was resistant to florpyrauxifen-benzyl (FPB), cyhalofop-butyl (CHB), and penoxsulam (PEX). This population carried an Ala-122-Asn mutation in the acetolactate synthase (ALS) gene but no mutation in acetyl-CoA carboxylase (ACCase) and transport inhibitor response1 (TIR1) genes. The metabolism rate of PEX was 2-fold higher, and the production of florpyrauxifen-acid and cyhalofop-acid was lower in the resistant population. Malathion and 4-chloro-7-nitrobenzoxadiazole (NBD-Cl) could reverse the resistance, suggesting that cytochrome P450 (CYP450) and glutathione S-transferase (GST) contribute to the enhanced metabolism. According to RNA-seq and qRT-PCR validation, two CYP450 genes (CYP71C42 and CYP71D55), one GST gene (GSTT2), two glycosyltransferase genes (rhamnosyltransferase 1 and IAAGLU), and two ABC transporter genes (ABCG1 and ABCG25) were induced by CHB, FPB, and PEX in the resistant population. This study revealed that the target mutant and enhanced metabolism were involved in the MHR mechanism in E. crus-galli.

Correction for Chen et al., "Repurposing a human acetyl-CoA carboxylase inhibitor firsocostat to treat fungal candidiasis alone and in combination".

Correction for Chen et al., "Repurposing a human acetyl-CoA carboxylase inhibitor firsocostat to treat fungal candidiasis alone and in combination".

Revisiting liver metabolism through acetyl-CoA carboxylase inhibition

Liver-targeted acetyl-coenzyme A (CoA) carboxylase (ACC) inhibitors in metabolic dysfunction-associated steatotic liver disease (MASLD) trials reveal notable secondary effects: hypertriglyceridemia and altered glucose metabolism, paradoxically with reduced hepatic steatosis. In their study, Deja et al. explored how hepatic ACC influences metabolism using different pharmacological and genetic methods, coupled with targeted metabolomics and stable isotope-based tracing techniques.

The GPR40 novel agonist SZZ15-11 improves non-alcoholic fatty liver disease by activating the AMPK pathway and restores metabolic homeostasis in diet-induced obese mice.

Non-alcoholic fatty liver is the most common cause of chronic liver disease. GPR40 is a potential therapeutic target for energy metabolic disorders. GPR40 is a potential therapeutic target for energy metabolic disorders. SZZ15-11 is a newly synthesized GPR40 agonist. In this study, we estimate the potency of SZZ15-11 in fatty liver treatment. In vivo, diet-induced obese (DIO) mice received SZZ15-11 (50 mg/kg) and TAK875 (50 mg/kg) for 6 weeks. Blood glucose and lipid, hepatocyte lipid and liver morphology were analysed. In vitro, HepG2 cells and GPR40-knockdown HepG2 cells induced with 0.3 mM oleic acid were treated with SZZ15-11. Triglyceride and total cholesterol of cells were measured. At the same time, the AMPK pathway regulating triglycerides and cholesterol esters synthesis was investigated via western blot and quantitative polymerase chain reaction in both liver tissue and HepG2 cells. SZZ15-11 was found to not only attenuate hyperglycaemia and hyperlipidaemia but also ameliorate fatty liver disease in DIO mice. At the same time, SZZ15-11 decreased triglyceride and total cholesterol content in HepG2 cells. Whether examined in the liver of DIO mice or in HepG2 cells, SZZ15-11 upregulated AMPKα phosphorylation and then downregulated the expression of the cholesterogenic key enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase and inhibited acetyl-CoA carboxylase activity. Furthermore, SZZ15-11 promotes AMPK activity via [cAMP]i accumulation. This study confirmed that SZZ15-11, a novel GPR40 agonist, improves hyperlipidaemia and fatty liver, partially via Gs signalling and the AMPK pathway in hepatocytes.

Molecular cloning and gene expression of acc2 from grass carp (Ctenopharyngodon idella) and the regulation of glucose metabolism by ACCs inhibitor.

Acetyl-CoA carboxylase (ACC) catalyzes the carboxylation of acetyl-CoA to malonyl-CoA. Malonyl-CoA, which plays a key role in regulating glucose and lipid metabolism, is not only a substrate for fatty acid synthesis but also an inhibitor of the oxidation pathway. ACC exists as two isoenzymes that are encoded by two different genes. ACC1 in grass carp (Ctenopharyngodon idellus) has been cloned and sequenced. However, studies on the cloning, tissue distribution, and function of ACC2 in grass carp were still rare. The full-length cDNA of acc2 was 8537bp with a 7146bp open reading frame encoding 2381 amino acids. ACC2 had a calculated molecular weight of 268.209kDa and an isoelectric point of 5.85. ACC2 of thegrass carp shared the closest relationship with that of the common carp (Sinocyclocheilus grahami). The expressions of acc1 and acc2 mRNA were detected in all examined tissues. Theexpression level of acc1 was high in the brain and fat but absent in the midgut and hindgut. Theexpression level of acc2 in the kidney was significantly higher than inother tissues, followed by the heart, brain, muscle, and spleen. ACCs inhibitor significantly reduced the levels of glucose, malonyl-CoA, and triglyceride in hepatocytes. This study showed that the function of ACC2 was evolutionarily conserved from fish to mammals. ACCs inhibitor inhibited the biological activity of ACCs, and reduced fat accumulation in grass carp.

Hepatic malonyl-CoA synthesis restrains gluconeogenesis by suppressing fat oxidation, pyruvate carboxylation, and amino acid availability

Acetyl-CoA carboxylase (ACC) promotes prandial liver metabolism by producing malonyl-CoA, a substrate for de novo lipogenesis and an inhibitor of CPT-1-mediated fat oxidation. We report that inhibition of ACC also produces unexpected secondary effects on metabolism. Liver-specific double ACC1/2 knockout (LDKO) or pharmacologic inhibition of ACC increased anaplerosis, tricarboxylic acid (TCA) cycle intermediates, and gluconeogenesis by activating hepatic CPT-1 and pyruvate carboxylase flux in the fed state. Fasting should have marginalized the role of ACC, but LDKO mice maintained elevated TCA cycle intermediates and preserved glycemia during fasting. These effects were accompanied by a compensatory induction of proteolysis and increased amino acid supply for gluconeogenesis, which was offset by increased protein synthesis during feeding. Such adaptations may be related to Nrf2 activity, which was induced by ACC inhibition and correlated with fasting amino acids. The findings reveal unexpected roles for malonyl-CoA synthesis in liver and provide insight into the broader effects of pharmacologic ACC inhibition.

AMP-activated protein kinase activation suppresses leptin expression independently of adipogenesis in primary murine adipocytes.

Adipogenesis, defined as the development of mature adipocytes from stem cell precursors, is vital for the expansion, turnover and health of adipose tissue. Loss of adipogenic potential in adipose stem cells, or impairment of adipogenesis is now recognised as an underlying cause of adipose tissue dysfunction and is associated with metabolic disease. In this study, we sought to determine the role of AMP-activated protein kinase (AMPK), an evolutionarily conserved master regulator of energy homeostasis, in adipogenesis. Primary murine adipose-derived stem cells were treated with a small molecule AMPK activator (BI-9774) during key phases of adipogenesis, to determine the effect of AMPK activation on adipocyte commitment, maturation and function. To determine the contribution of the repression of lipogenesis by AMPK in these processes, we compared the effect of pharmacological inhibition of acetyl-CoA carboxylase (ACC). We show that AMPK activation inhibits adipogenesis in a time- and concentration-dependent manner. Transient AMPK activation during adipogenic commitment leads to a significant, ACC-independent, repression of adipogenic transcription factor expression. Furthermore, we identify a striking, previously unexplored inhibition of leptin gene expression in response to both short-term and chronic AMPK activation irrespective of adipogenesis. These findings reveal that in addition to its effect on adipogenesis, AMPK activation switches off leptin gene expression in primary mouse adipocytes independently of adipogenesis. Our results identify leptin expression as a novel target of AMPK through mechanisms yet to be identified.

Investigation of pharmacokinetic drug interaction between clesacostat and DGAT2 inhibitor ervogastat in healthy adult participants.

Co-administration of clesacostat (acetyl-CoA carboxylase inhibitor, PF-05221304) and ervogastat (diacylglycerol O-acyltransferase inhibitor, PF-06865571) in laboratory models improved non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) end points and mitigated clesacostat-induced elevations in circulating triglycerides. Clesacostat is cleared via organic anion-transporting polypeptide-mediated hepatic uptake and cytochrome P450 family 3A (CYP3A); invitro clesacostat is identified as a potential CYP3A time-dependent inactivator. Invitro ervogastat is identified as a substrate and potential inducer of CYP3A. Prior to longer-term efficacy trials in participants with NAFLD, safety and pharmacokinetics (PK) were evaluated in a phase I, non-randomized, open-label, fixed-sequence trial in healthy participants. In Cohort 1, participants (n = 7) received clesacostat 15 mg twice daily (b.i.d.) alone (Days 1-7) and co-administered with ervogastat 300 mg b.i.d. (Days 8-14). Mean systemic clesacostat exposures, when co-administered with ervogastat, decreased by 12% and 19%, based on maximum plasma drug concentration and area under the plasma drug concentration-time curve during the dosing interval, respectively. In Cohort 2, participants (n = 9) received ervogastat 300 mg b.i.d. alone (Days 1-7) and co-administered with clesacostat 15 mg b.i.d. (Days 8-14). There were no meaningful differences in systemic ervogastat exposures when administered alone or with clesacostat. Clesacostat 15 mg b.i.d. and ervogastat 300 mg b.i.d. co-administration was overall safe and well tolerated in healthy participants. Cumulative safety and no clinically meaningful PK drug interactions observed in this study supported co-administration of these two novel agents in additional studies exploring efficacy and safety in the management of NAFLD.

Low phosphorus increases hepatic lipid deposition, oxidative stress and inflammatory response via Acetyl-CoA carboxylase-dependent manner in zebrafish liver cells

Acetyl-CoA carboxylase (ACC) plays a regulatory role in both fatty acid synthesis and oxidation, controlling the process of lipid deposition in the liver. Given that existing studies have shown a close relationship between low phosphorus (P) and hepatic lipid deposition, this study was conducted to investigate whether ACC plays a crucial role in this relationship. Zebrafish liver cell line (ZFL) was incubated under low P medium (LP, P concentration: 0.77 mg/L) or adequate P medium (AP, P concentration: 35 mg/L) for 240 h. The results showed that, compared with AP-treated cells, LP-treated cells displayed elevated lipid accumulation, and reduced fatty acid β-oxidation, ATP content, and mitochondrial mass. Furthermore, transcriptomics analysis revealed that LP-treated cells significantly increased lipid synthesis (Acetyl-CoA carboxylases (acc), Stearyl coenzyme A dehydrogenase (scd)) but decreased fatty acid β-oxidation (Carnitine palmitoyltransferase I (cptI)) and (AMP-activated protein kinase (ampk)) mRNA levels compared to AP-treated cells. The phosphorylation of AMPK and ACC, and the protein expression of CPTI were significantly decreased in LP-treated cells compared with those in AP-treated cells. After 240 h of LP treatment, PF-05175157 (an ACC inhibitor) was supplemented in the LP treatment for an additional 12 h. PF-05175157-treated cells showed higher phosphorylation of ACC, higher protein expression of CPTI, and lower protein expression of FASN, lower TG content, enhanced fatty acid β-oxidation, increased ATP content, and mitochondrial mass compared with LP-treated cells. PF-05175157 also relieved the LP-induced oxidative stress and inflammatory response. Overall, these findings suggest that ACC is a promising target for treating LP-induced elevation of lipid deposition in ZFL, and can alleviate oxidative stress and inflammatory response.

Management of Herbicide resistant Phalaris minor: A Review

Littleseed canarygrass (Phalaris minor Retz), an annual species of the family Poaceae, is a major weed problem in many wheat-producing countries. The excessive dependence on herbicides for its control led to the evolution of multiple herbicides resistance and yield losses. The first case of resistant P. minor in India was to the Photosystem-II inhibitor isoproturon in the early 1990’s. P. minor has been found resistant to Acetolactate Synthase (ALS) inhibitors, Acetyl-CoA Carboxylase (ACCase) inhibitors, Photosystem II inhibitors. It is highly competitive and in severe cases can cause complete crop failure, forcing farmers to harvest their crop as fodder or ploughing the standing crop along with weeds. For management of these multiple herbicide resistant P. minor, pyroxasulfone, pendimethalin, flumioxazin, trifluralin and flufenacet can be used as alternative herbicides. Moreover, in-depth biological and ecological studies on P. minor should be carried out for devising integrated weed management strategies. The long-term strategies of efficient weed management and sustainability of wheat production should include the use of alternative herbicides, herbicide mixture, crop rotation along with other non-chemical methods like manual removal of weeds, mulching, Summer ploughing etc providing the competitive advantages to the wheat crop over P. minor, at the same time increasing the profitability of the farmer by controlling the weed effectively and reducing the selection pressure on the weeds which will inturn reduce the resistance development in weeds

Repurposing a human acetyl-CoA carboxylase inhibitor firsocostat to treat fungal candidiasis alone and in combination.

Opportunistic fungal infections, particularly caused by Candida albicans, remain a common cause of high morbidity and mortality in immunocompromised patients. The escalating prevalence of antifungal drug resistance necessitates the immediate exploration of alternative treatment strategies to combat these life-threatening fungal diseases. In this study, we investigated the antifungal efficacy of firsocostat, a human acetyl-CoA carboxylase (ACC) inhibitor, against C. albicans. Firsocostat alone displayed moderate antifungal activity, while combining it with voriconazole, itraconazole, or amphotericin B exhibited synergistic effects across almost all drug-sensitive and drug-resistant C. albicans strains tested. These observed synergies were further validated in two mouse models of oropharyngeal and systemic candidiasis, where the combination therapies demonstrated superior fungicidal effects compared to monotherapy. Moreover, firsocostat was shown to directly bind to C. albicans ACC and inhibit its enzymatic activity. Sequencing spontaneous firsocostat-resistant mutants revealed mutations mapping to C. albicans ACC, confirming that firsocostat has retained its target in C. albicans. Overall, our findings suggest that repurposing firsocostat, either alone or in combination with other antifungal agents, holds promising potential in the development of antifungal drugs and the treatment of candidiasis.

Retraction: Hypothalamic Inhibition of Acetyl-CoA Carboxylase Stimulates Hepatic Counter-Regulatory Response Independent of AMPK Activation in Rats.

Retraction: Hypothalamic Inhibition of Acetyl-CoA Carboxylase Stimulates Hepatic Counter-Regulatory Response Independent of AMPK Activation in Rats.

Convergent Syntheses of Isomeric Imidazolospiroketones as Templates for Acetyl-CoA Carboxylase (ACC) Inhibitors.

The synthesis of imidazole fused spirocyclic ketones as templates for acetyl-CoA carboxylase (ACC) inhibitors is reported. By completing the spirocyclic ring closure via divergent pathways, the synthesis of these regioisomers from common intermediates was developed. Through an aldehyde homologation/transmetalation strategy, one isomer was formed selectively. The second desired isomer was obtained via an intramolecular aromatic homolytic substitution reaction. Preparation of these isomeric spiroketones provided templates which, upon elaboration, led to key structure-activity relationship (SAR) points for delivery of potent ACC inhibitors.

Effect of Green and Red Thai Kratom (Mitragyna speciosa) on pancreatic digestive enzymes (alpha-glucosidase and lipase) and acetyl-carboxylase 1 activity: A possible therapeutic target for obesity prevention.

Regular use of Thai kratom has been linked to reduced blood triglyceride levels and body mass index (BMI) in healthy individuals. We analyzed Green Thai Kratom (GTK) and Red Thai Kratom (RTK) to investigate their effects on pancreatic digestive enzymes. The ethanol extracts of GTK and RTK inhibited lipase activity more strongly than alpha-glucosidase activity, suggesting the presence of lipase inhibitors. Mitragynine, the major compound in GTK, showed potent lipase inhibition and moderate alpha-glucosidase inhibition. Quercetin, found in both extracts, strongly inhibited alpha-glucosidase but had limited effects on lipase. These findings suggest that mitragynine and quercetin may hinder triglyceride and starch digestion. Combination inhibition studies revealed synergistic effects between mitragynine and quercetin on alpha-glucosidase activity. Additionally, both GTK and RTK extracts reduced fat accumulation in 3T3-L1 adipocyte cells, with quercetin specifically inhibiting Acetyl-CoA carboxylase 1 (ACC1), a key enzyme in fatty acid biosynthesis. Thus, GTK and RTK extracts, particularly mitragynine and quercetin, exhibit potential anti-obesity effects. We report the novel finding that Thai kratom inhibits de novo fatty acid synthesis by targeting ACC1, resulting in decreased fat accumulation in adipocytes. Regular use of Thai kratom in specific populations may improve blood triglyceride levels and reduce BMI by inhibiting lipase, alpha-glucosidase, and ACC1 activity. Further clinical trials are needed to determine optimal dosage, duration, toxicity levels, and potential side effects of Kratom use.

Fine-tuning gene expression of regulator AdmX for improved biosynthesis of andrimid in Erwinia persicina BST187.

Andrimid is a potent antibiotic that inhibits acetyl-CoA carboxylase. However, its low biological yield and complex chemical synthesis have hindered its large-scale application. In this study, we found that the LysR-type transcriptional activator AdmX controls andrimid yield by adjusting its expression level in the andrimid-producing bacterium Erwinia persicina strain BST187. Our results showed that gradually increasing of admX transcriptional levels significantly improved andrimid yield, while the yield declined when admX was overexpressed excessively. To further estimate the effect of AdmX on andrimid promotion, we fitted and developed a model which was y = -0.5576x2 + 61.945x + 800.63 (R2 = 0.9591), where x represents the admX transcriptional level and y represents andrimid yield. Andrimid yield of admX overexpression strain BST187ΔadmX/pET28a-Pgap-1::admX was greatly improved by 260%, which was reported for the first time that andrimid yield could be promoted by genetic engineering. Thus, this study provides important insights that the biosynthesis of andrimid would be improved by bioengineering and sheds lights on the potential application of andrimid in both biomedicine and bioagricultural manipulation with its large-scale production in the future. KEY POINTS: • Andrimid production can be greatly promoted by genetic engineering on non-model chassis. • The relationship between AdmX abundance and andrimid yield in Erwinia persicina strain BST187 might be parabolic. • Erwinia persicina BST187 combined with chassis modification enable the promising applications in andrimid industrialization.

Analysis of multi-disease targeting effect of phytochemicals by AMPK stimulation– diabetes: A computational approach

Diabetes is a silent killer and a metabolic syndrome characterized by hyperglycemia that has been exponentially increasing in recent years. There is a need to develop therapeutic agents to control hyperglycemia and its secondary complications as well as protect and revive beta cells in diabetic patients. The target for first-line diabetes treatment is the adenosine monophosphate protein kinase (AMPK), which participates in cellular energy metabolism through phosphorylation of metabolic enzymes and transcription regulators. This study examined the drug-related properties as well as lead preparation of Catharanthus roseus alkaloids and testing molecular interaction at the AMPK targets to confirm their anti-diabetic effect. A control drug metformin and a library of 85 molecules of C. roseus alkaloids were crossed with the ADMET test, followed by the investigation of molecular interaction tested on AMPK1 and AMPK2 targets through an in silico docking process. Vindolinine (CID: 24148538), vindoline (CID: 425978), (+)-vindorosine (CID: 261578), Cr-1 (CID: 5315746), and Cr-2 (CID: 59908094) had passed the ADMET test. Molecular interaction of the tested C. roseus alkaloids on AMPK1 and AMPK2 targets had potential energy that varied from −7.4 to −5.3 kcal/mol, whereas binding energies of −4.0 kcal/mol for AMPK1-metformin interaction and −4.2 kcal/mol for AMPK2-metformin interaction were observed. The tested C. roseus alkaloids were shown to be more potent activators of AMPK than the control drug. All five biomolecules of C. roseus acted as modulators that have the potential to stimulate AMPK, reduce glucose production, and increase glucose utilization in hepatocytes. In addition, they diminished insulin resistance and secondary complications of diabetes by inhibiting acetyl-CoA carboxylase, regulating cholesterol levels and macrophage, and reviving beta cells in Type 2 diabetes. These results provided the foundation for developing new multi-disease-targeting drugs that can treat diabetes, obesity, cardiovascular disease, cancer, and other diseases by the stimulation of AMPK1 and AMPK2 targets.

Cytochrome P450s-Involved Enhanced Metabolism Contributes to the High Level of Nicosulfuron Resistance in Digitaria sanguinalis from China.

Large crabgrass (Digitaria sanguinalis (L.) Scop.) is one of the major malignant grass weeds in Chinese maize (Zea mays L.) fields, and it has recently developed resistance to the acetolactate synthase (ALS)-inhibiting herbicide nicosulfuron. This study focused on a suspected nicosulfuron-resistant (R) population (LJ-01) of D. sanguinalis, collected from Lujiang County in Anhui Province, China, to explore the resistance level and potential resistance mechanism. Whole-plant dose-response testing confirmed that the LJ-01 population evolved a high level of resistance to nicosulfuron (11.5-fold) compared to the susceptible (S) population, DY-02. The ALS gene sequencing and relative expression assay of the R plants indicated that target gene mutation and overexpression were not responsible for the resistance phenotype. However, pretreatment with malathion, a known cytochrome P450 monooxygenase (P450) inhibitor, alleviated the resistance of the R population to nicosulfuron by approximately 36%. High-performance liquid chromatography (HPLC) analysis revealed that the R plants metabolized nicosulfuron faster than the S plants. Moreover, cross-resistance testing suggested that the R population exhibited low levels of resistance to thifensulfuron-methyl and pyrazosulfuron-ethyl, but it remained susceptible to rimsulfuron. Multiple resistance patterns showed that the R population evolved low resistance to the photosystem inhibitors bromoxynil octanoate and atrazine and sensitivity to the acetyl-CoA carboxylase (ACCase) inhibitor cyhalofop-butyl and the 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors tembotrione, mesotrione, and topramezone. This study reports, for the first time, the simultaneous resistance to ALS and different photosystem inhibitors in D. sanguinalis. The nicosulfuron resistance observed in the R population could primarily be attributed to an enhanced metabolism involving P450 enzymes.

Emerging possibilities in the advancement of herbicides to combat acetyl-CoA carboxylase inhibitor resistance

Acetyl-CoA carboxylase (ACCase: EC 6.4.1.2) is one of the essential biotins containing enzymes required by plants for fatty acid synthesis and elongation. The unique enzyme is present in its homomeric form in all the Gramineae family, making it a suitable target for developing herbicides selectively against weeds of the Gramineae family. One such example is infestation of Phalaris minor in winter wheat crop fields, where aryloxyphenoxypropionates (FOP); cyclohexanediones (DIM) and phenyl pyrazoline (DEN) group of ACCase inhibiting herbicides are used. However, the increasing number of ACCase herbicide resistant weed populations has compelled agro-scientists to seek varied possibilities for weed control, through Integrated Weed Management (IWM) strategies. Developing new potential herbicides to regain sensitivity in weeds could be an approach to weed control. The current advancement in computational techniques could be of aid in developing new herbicide-like molecules by exploring the genomics, proteomics and structural details of catalytic sites of herbicide action in crops as well as weeds.

ACCase gene mutations and P450-mediated metabolism contribute to cyhalofop-butyl resistance in Eleusine indica biotypes from direct-seeding paddy fields

Eleusine indica causes problems in direct-seeding rice fields across Jiangsu Province in China. Long-term application of chemical herbicides has led to the widespread evolution of resistance in E. indica. In this study, we surveyed the resistance level of cyhalofop-butyl (CyB) in 19 field-collected E. indica biotypes, and characterized its underlying resistance mechanisms. All 19 biotypes evolved moderate- to high-level resistance to CyB (from 5.8- to 171.1-fold). 18 biotypes had a target-site mechanism with Trp-1999-Ser, Trp-2027-Cys, or Asp-2078-Gly mutations, respectively. One biotype (JSSQ-1) was identified to have metabolic resistance, in which malathion pretreatment significantly reduced the CyB resistance, and cyhalofop acid was degraded 1.7- to 2.5-times faster in this biotype compared with a susceptible control. Furthermore, the JSSQ-1 biotype showed multiple resistance to acetyl-CoA carboxylase (ACCase) inhibitor metamifop (RI = 4.6) and fenoxaprop-p-ethyl (RI = 5.1), acetolactate synthase (ALS) inhibitor imazethapyr (RI = 4.1), and hydroxyphenylpyruvate dioxygenase (HPPD) inhibitor mesotrione (RI = 3.5). In addition, 11 out of 19 E. indica biotypes exhibited multiple resistance to glyphosate. This research has identified the widespread occurrence of CyB resistance in E. indica, attributed to target-site mutations or enhanced metabolism. Moreover, certain biotypes have exhibited resistance to multiple herbicides or even cross-resistance. Consequently, there is an urgent need to implement diverse weed management practices to effectively combat the proliferation of this weed in rice fields.

849-P: Antidiabetic Effects of TLC-3595, a Selective ACC2 Inhibitor, in ZDF Rats

Background: TLC-3595 is a potent (IC50=14nM), selective, small molecule, allosteric inhibitor of acetyl-CoA carboxylase 2 (ACC2). TLC-3595 provides a novel therapeutic approach for type 2 diabetes (T2D), via reduction in intramyocellular lipid (IMCL) content, that is complementary to approved therapies. Reduced IMCL strongly correlates with insulin sensitivity (IS). Here, we demonstrate antidiabetic effects of TLC-3595 in Zucker Diabetic Fatty (ZDF) rats. Methods: IMCL was measured by 1H-MRS. T2D progression and IS by hyperinsulinemic-euglycemic clamp were assessed in 30% diet-restricted ZDF rats treated with TLC-3595 (1.67, 5, or 15mg/kg) or pioglitazone (Pio, 0.75mg/kg) daily for 5-12 weeks. Results: TLC-3595 or an analog caused rapid and sustained IMCL reduction (~50%) in lean and dysmetabolic rodents. TLC-3595 enhanced systemic fatty acid oxidation (increased plasma beta-hydroxybutyrate) and reduced cardiac lipid in ZDF rats. TLC-3595 dose-dependently delayed β-cell failure in ZDF rats and was non-inferior to Pio for reductions in hyperglycemia (15-25% lower glucose AUC) and HbA1c (0.6-1.6% vs. vehicle) (Fig A, B). TLC-3595 improved IS and increased clamp glucose infusion rate by 29%, (Fig C). Conclusion: TLC-3595 reduced IMCL, improved IS, and delayed T2D progression comparable to Pio in ZDF rats. These data provide strong rationale for evaluation of TLC-3595 to treat insulin resistance and T2D. Disclosure A. Vijayakumar: Employee; OrsoBio Inc, Gilead Sciences, Inc. E. Murakami: Employee; OrsoBio. R.S. Huss: Employee; OrsoBio, Inc. Stock/Shareholder; OrsoBio, Inc. N. Sroda: None. A. Shimazaki: Employee; Shionogi & Co. Ltd. Y. Kashiwagi: Employee; Shionogi & Co. Ltd. R.P. Myers: Employee; OrsoBio, Inc. Stock/Shareholder; OrsoBio, Inc. M. Subramanian: Other Relationship; OrsoBio Inc. G.I. Shulman: Other Relationship; AstraZeneca, Merck & Co., Inc., Janssen Research & Development, LLC. Consultant; Novo Nordisk. Other Relationship; iMetabolic Biopharma Corporation, Maze Therapeutics, 89bio, Inc. Consultant; DiCerna Pharmaceuticals, Inc. Other Relationship; Equator Therapeutics, Inc., Generian Pharmaceuticals. Stock/Shareholder; Levels Health, Inc. Other Relationship; Fortress Biotech, Inc. Consultant; Bayer Consumer Care AG, Kriya Therapeutics, Arrowhead Pharmaceuticals, Inc., ESPERION Therapeutics, Inc. Other Relationship; OrsoBio, Aro Biotherapeutics Company.