The db/db mouse (db stands for diabetes) [18] can be used to study the molecular basis of obesity; however, it is commonly used for studies concerning type 2 diabetes [19]. These db/db mice were developed by investigators from the Jackson Laboratories in 1966 and are phenotypically similar to the ob/ob mouse model. They exhibit a mutation in leptin receptor gene, in an autosomal recessive trait that encodes for a G-to-T point mutation, leading to defective leptin signaling [19,20]. The predominant mouse strain in which this mutation is maintained is the C57BL/KS [14,19]. The db/db mice are characterized by hyperphagia, a consequence of impaired leptin signing in the hypothalamus, develop early-onset obesity due to low energy expenditure, are insulin resistant, have decreased insulin levels and are hypothermic. Moreover, they develop dyslipidemia, hypogonadism, hyperglycemia, have growth hormone (GH) deficiency, and are infertile [18,20]. Regarding the analysis of natural products on obesity development, this model can become an option, especially when the compounds that are tested, such as Artemisia extract (artemether) and barley (Table 1), have supposedly a double effect on both obesity and diabetes [21,22].

Developed at Jackson Laboratories in 1966, the ob/ob mice are homozygous for the obese spontaneous mutation in the leptin gene that prevents the secretion of bioactive leptin resulting in leptin deficiency [1,14,18]. Leptin is a hormone derived from adipocytes, and its deficiency leads to an increase in appetite and the development of severe obesity [23,24,25]. The homozygous mutant mice are typically of the C57BL/6J strain. These mice present a pronounced obese phenotype characterized by uncontrollable food intake, type 2 diabetes, hyperphagia, hyperleptinemia, insulin resistance and fatty liver, hepatic steatosis, hypogonadism, and hypothyroidism [19,20]. The ob/ob mice are a better model for studying obesity than db/db mice because they have a longer lifetime and fewer clinical signs [26]. The effects of natural compounds such as celastrol, genistein, cannabinoid Δ9-tetrahydrocannabivarin and cinnamon extract on the ob/ob mouse model can be analyzed in Table 1 [27,28,29,30].

The Zucker fatty rat (ZFR), or Zucker (fa/fa), has a similar phenotype to ob/ob and db/db mice, as it has a homozygous missense mutation (fatty, fa) in the long form of the leptin receptor, which makes it insensitive to leptin [31,32]. Defects in the leptin receptor caused by this mutation result in the development of early-onset obesity due to hyperphagia, reducing the energy expenditure and leading to morbid obesity [14]. These rats are less likely to acquire diabetes, although ZFR has a high level of insulin resistance and fertility is reduced [14,20]

The ZFR is the most used model for studying several genetic characteristics associated with obesity [33,34], although it has also been used to study the anti-obesogenic effects of natural compounds such as the extracts of red wine [35], rosemary [36], green tea [37], bilberries, and purple potatoes [38] (Table 1).

The Otsuka Long-Evans Tokushima fatty (OLETF) rat is a spontaneous cholecystokinin type A (CCK-A) receptor knockout and does not respond to CCK, a peptide-derived hormone that functions as a peripheral satiety signal [20,39]. As a result, these rats are hyperphagic beginning several weeks after birth and develop mild obesity [34], which is a consequence of increased food intake and meal sizes, leading to an increase in body weight [40]. Moreover, OLETF rats develop diabetes, which manifests as polyuria and polydipsia [20]. At approximately 8 weeks of age, OLETF rats display hyperinsulinemia, and insulin resistance is observed at 12 weeks of age. Later, hyperplasia of pancreatic islets and hypertriglyceridemia develop [18].

The effects of gambigyeongsinhwan [41], gyeongshingangjeehwan [42], fermented mushroom milk-supplemented dietary fiber [43], or soy β-conglycinin [44] on obesity were evaluated in this animal model (Table 1).

The VMH nucleus, located in the hypothalamus, is associated with the regulation of eating behavior and satiety, with the use of rats with VMH lesions being one of the first models developed to induce obesity in rodents [14,20,45]. Bilateral lesions of the VMH nucleus lead to the development of hyperphagia, vagal hyperactivity, sympathetic hypoactivity, enlarged pancreatic islets, and hyperinsulinemia and can be caused by using the neurotoxin MSG [46,47]. MSG administration also causes lesions in the arcuate nucleus of the hypothalamus and circumventricular neurons. To induce obesity, MSG can be administered subcutaneously or intraperitoneally (2–4 mg/g of body weight) during the neonatal period, 4–10 times [48]. Adult rats who received MSG in the neonatal period developed endocrine dysfunction syndromes, which are characterized by obesity development, disturbances in the regulation of caloric balance, reduced growth, behavioral changes, and hypogonadism [47,49]. This obesity model was used to study the anti-obesogenic effects of Roselle (Hibiscus sabdariffa L.) [50] (Table 1).

Diet-induced obesity (DIO) rodent models are achieved by exposing rats and mice to specific diets that induce obesity, thereby reproducing dietary imbalances that are often the main cause of obesity in humans [13,20,52,53]. The main advantage of diets is that they can be standardized and control the nutrient percentages. There are a variety of diets that can be used for this purpose, such as high-fat diets (HFD), high-sugar diets (HSD), and high-sugar and high-fat (HSHF) diets, known as Western diets [16]. The HFD-induced obesity mouse model is one of the most used to understand the relationship between hyperlipidemic diets and the pathophysiology of obesity [52]. Within mouse strains, there are some more susceptible to DIO than others [13,54]; for example, the inbred C57BL/6 mouse strain is highly susceptible in contrast to SWR/J, A/J and CAST/Ei mouse strains, which tend to be resistant to these diets. In fact, the C57BL/6J mouse strain is the most used since when they are fed with HFD, these animals develop characteristics similar to humans with complex metabolic syndrome, such as obesity, high fat accumulation, insulin resistance, hyperglycemia, hyperlipidemia, hypertension, non-alcoholic fatty liver disease, and endothelium damage associated with cardiovascular diseases [18,20,52,55,56]. Some rat strains can also be used as models of HFD-induced obesity, such as the outbred Sprague Dawley, Wistar, or Long Evans rats [14]. However, Sprague Dawley rats showed diverse responses, with some animals showing DIO, while others showed resistance to the diet [13].