Novel dual PPARα/γ agonists protect against liver steatosis and improve insulin sensitivity while avoiding side effects
Abstract
Insulin resistance is a feature of type 2 diabetes mellitus (T2D), and is strongly interconnected with non-alcoholic fatty liver disease (NAFLD). Peroxisome-proliferator activated receptor gamma (PPARγ) and peroxisome-proliferator activated receptor alpha (PPARα) are master regulators of insulin sensitivity and lipid metabolism, respectively. Thiazolidinediones (TZDs) such as pioglitazone, which target PPARα/γ, are highly effective at treating insulin resistance and NAFLD, but their clinical utility has been restricted by side effects such as weight gain, adipocyte hypertrophy and fluid retention. Therefore, there is urgent need for new safer and effective drugs. Thus, we aimed to develop novel dual PPARα/γ agonists to avoid their known side effects while preserving their overall therapeutic effects. Here, we show that our novel agonists G4 and G5 strongly stimulate glucose transporter 4 (GLUT4) translocation to the cell membrane in skeletal muscle cells, and manifest weaker lipogenic effect in adipocytes. Moreover, G4 and G5 improve systemic glucose metabolism, hyperinsulinemia, hyperlipidemia, and markers of liver injury in high fructose diet-induced insulin resistant rats. Mechanistic studies revealed that G4 and G5 enhance GLUT4, and AMPK in skeletal muscle and protect against liver steatosis by upregulating PPARα and improve whole-body insulin sensitivity by increasing PPARγ. Despite this increase in PPARγ activity, G4 and G5 inhibit the unwanted side effects such as weight gain due to adiposity, hypertrophy of adipocytes, and fluid retention unlike TZDs. These findings identify G4 and G5 as promising dual PPARα/γ agonists for the treatment of NAFLD and insulin resistance with improved safety.
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Pioglitazone is a calorie restriction mimetic to ameliorate steatosis, but with unwanted side effects.
“Not incidentally, PIO is a CRM to ameliorate steatosis; however, with unwanted side effects [91].”
From Molecular Targets of 20-Hydroxyecdysone in Mammals, Mechanism of Action: Is It a Calorie Restriction Mimetic and Anti-Aging Compound? (2025) · cites this paper as [91]
The effect of 20E in ovariectomized rats fed a thigh-fat, high-fructose diet was similar to that of Pioglitazone, a PPAR-γ agonist.
“This effect was similar to that of Pioglitazone (PIO), a peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonist.”
From Molecular Targets of 20-Hydroxyecdysone in Mammals, Mechanism of Action: Is It a Calorie Restriction Mimetic and Anti-Aging Compound? (2025) · cites this paper as [91]
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“This e ff ect was similar to that of Pioglitazone (PIO), a peroxisome proliferator-activated receptor-gamma ( Not incidentally, PIO is a CRM to ameliorate steatosis; however, with unwanted side effects [91].”
- Authors
- Guru, B., Tamrakar, A. K., Manjula, S. N., & Prashantha Kumar, B. R.
- Affiliations
- Central Drug Research Institute (IN)
- JSS Academy of Higher Education and Research (IN)
- Venue
- European Journal of Pharmacology
- Publisher
- Elsevier BV
- Published
- 2022-11
- Volume
- 935
- Pages
- 175322
- ISSN
- 0014-2999 (ISSN-L)
- OpenAlex
- W4304124312
- Cited by
- 18
- References
- 66
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 4 · 2023: 1
- FWCI
- 1.14
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- European Journal of Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Hospital for Sick Children
- Cipla
- Indian Council of Medical Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- non-alcoholic fatty liver disease, hepatic steatosis, insulin resistance, type 2 diabetes, thiazolidinediones, GLUT4 translocation, skeletal muscle glucose metabolism, AMPK, adipocyte hypertrophy, fluid retention, weight gain, high-fructose diet, drug safety
- MeSH terms
- Animals, Diabetes Mellitus, Type 2, Hypertrophy, Insulin Resistance, Weight Gain, Thiazolidinediones, PPAR alpha, PPAR gamma, Rats, Non-alcoholic Fatty Liver Disease
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