Obesity is a complex, multifactorial disease characterized by excessive fat accumulation, leading to various health problems. A 22-year study showed a 13.99% increase in age-adjusted obesity prevalence. Obesity is a major risk factor for metabolic disorders, cardiovascular disease, gastrointestinal issues, and type 2 diabetes (T2DM). Obesity develops when energy intake surpasses energy expenditure, with excess energy stored as triglycerides in white adipose tissue (WAT). The conversion of WAT involves changes in adipose tissue macrophages (ATMs). M1 macrophages promote inflammation and insulin resistance, while M2 macrophages promote thermogenesis in brown adipose tissue (BAT), contributing to energy balance and reducing obesity. Hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase is an enzyme in cholesterol biosynthesis; its inhibition by statins reduces cholesterol synthesis and improves insulin sensitivity. Statin use, however, has limitations. Phytochemicals, such as geraniol (an acyclic monoterpene), offer potential benefits due to their immunomodulatory, anti-inflammatory, and neuroprotective effects. Geraniol also inhibits HMG-CoA reductase and demonstrates hypoglycemic effects in diabetic rat models. This study aims to evaluate geraniol's effects on obesity.

The literature extensively documents the global increase in obesity and its associated health risks. Studies highlight the role of energy imbalance and WAT accumulation in obesity development. The importance of ATMs in the pathogenesis of obesity and T2DM is emphasized, with M1 macrophages contributing to inflammation and insulin resistance and M2 macrophages promoting thermogenesis and improved metabolic health. The role of HMG-CoA reductase and its inhibition in cholesterol metabolism and insulin sensitivity is discussed. Previous research demonstrated that statins effectively reduced cholesterol and improved insulin sensitivity but have associated side effects. The researchers examined previous studies on geraniol and its promising effects as an immunomodulatory, anti-inflammatory, neuroprotective, and hypoglycemic agent with HMG-CoA reductase inhibitory activity.

Thirty male Albino Wistar rats (180-200 g) were divided into five groups: normal control, negative control (HFD-fed), geraniol 200 mg/kg, geraniol 400 mg/kg, and atorvastatin (standard) 5 mg/kg. Obesity was induced by feeding rats with a high-fat diet (HFD) for four weeks (excluding the normal control). After four weeks, blood glucose was measured. Geraniol and atorvastatin treatment was initiated for the next four weeks. Blood glucose was measured again, and an oral glucose tolerance test (OGTT) was performed. Feed intake and body weight were monitored weekly. Blood samples were collected for glucose and lipid profile analysis. Adipose tissue (interscapular WAT, BAT, subcutaneous, epididymal, inguinal, mesenteric, triceps, intraperitoneal) and organs (liver, pancreas, heart) were isolated and weighed. Oxidative stress markers (MDA and SOD) were assessed in liver tissue homogenates. Histopathological analysis was performed on heart, pancreas, and adipose tissue. In silico molecular docking was performed using Autodock 4.2 to study the interaction of geraniol with HMG-CoA reductase (PDB ID: 1HWK). Data were analyzed using one-way ANOVA and two-way repeated measures ANOVA with post-hoc tests. p<0.05 was considered statistically significant.

Geraniol treatment significantly reduced body weight in HFD-induced obese rats without affecting feed intake. Geraniol significantly improved blood glucose levels (both fasting and during OGTT) compared to the negative control. Geraniol significantly improved the lipid profile, reducing cholesterol, triglycerides, and LDL levels while increasing HDL levels. Geraniol significantly reduced the weight of adipose tissue depots from various body regions and reduced the weight of the liver, pancreas, and heart compared to the negative control. Geraniol ameliorated oxidative stress markers in the liver (reduced MDA and increased SOD). Histopathological examination showed that geraniol reversed the negative effects of HFD on heart and pancreas tissues (reduced hyaline degeneration in the heart and improved islet structure in the pancreas). Histology revealed that geraniol increased the number of BAT and decreased WAT in interscapular adipose tissue. In silico docking studies showed that geraniol interacted with HMG-CoA reductase with a binding energy of -5.13 kcal/mol, primarily interacting with ASP767 and GLN770 residues.

The study demonstrates that geraniol effectively combats HFD-induced obesity in rats. The reduction in body weight and improved glucose and lipid profiles highlight geraniol's positive impact on metabolic parameters. The decreased weight of adipose tissue and organs and the reversal of histopathological changes suggest that geraniol improves tissue health. The amelioration of oxidative stress further supports geraniol's protective effects. The in silico study confirms geraniol's interaction with HMG-CoA reductase, providing a potential molecular mechanism for its observed effects. The findings suggest that geraniol's ability to promote WAT to BAT conversion and its impact on HMG-CoA reductase activity contribute to its anti-obesity effects. These effects align with previous studies indicating that geraniol possesses anti-inflammatory, antioxidant and hypoglycaemic properties.

This study shows that geraniol significantly reduces obesity and improves related metabolic complications in HFD-induced obese rats. The mechanism appears to involve HMG-CoA reductase inhibition, leading to improvements in inflammatory and oxidative stress pathways, and promoting the conversion of WAT to BAT. These findings suggest that geraniol could be a promising natural compound for combating obesity and its associated complications. Future research could focus on clinical trials to evaluate geraniol's efficacy and safety in humans.

The study was conducted only in male rats, limiting the generalizability of the findings to female rats and humans. The study used a specific HFD model; different HFD compositions could yield varying results. The in silico study provides a potential mechanism but requires further in vivo validation. Long-term studies are necessary to assess the sustained effects of geraniol on weight management and metabolic parameters.