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ISSN : 1225-1577(Print)
ISSN : 2384-0900(Online)
The Korean Journal of Oral and Maxillofacial Pathology Vol.46 No.1 pp.1-11
DOI : https://doi.org/10.17779/KAOMP.2022.46.1.001

The Study of Human Obesity Using Drosophila Melanogaster as an Animal Model

Ji-Eun Jung1),2), Joo-Young Lee4), Ji-Hye Lee1),2),3),4)*
1)Department of Life Science in Dentistry
2)BK21 FOUR Project
3)Department of Oral Pathology, School of Dentistry
4)Dental and Life Science Institute, Pusan National University, Yangsan 50612, Korea
*Correspondence: Ji-Hye Lee, Department of Oral Pathology and Life Science in Dentistry, School of Dentistry, Pusan National University, 49 Pusandaehak-ro, Mulgeum-eup, Yangsan-si 50612, Republic of Korea Tel: +82-51-510-8259 Email: jihyelee@pusan.ac.kr
January 13, 2022 January 14, 2022 February 4, 2022

Abstract


The increasing prevalence of obesity is associated with various metabolic diseases such as diabetes, posing significant social and economic burdens to the society. While obesity is a complex disease with multiple factors contributing to its pathophysiology, altered glucose and lipid metabolism is evident in obese patients as well as in animal models. Abnormal metabolic regulation often leads to development of insulin resistance, a hallmark of obesity-induced type 2 diabetes. In this review, we provide a brief overview of altered lipid metabolism manifested in the obese state. In addition, two representative animal models, Mus musculus and Drosophila melanogaster, are presented with experimental approaches adopted for generation and utilization of these models. More specifically, Drosophila has been widely used for studying the core physiological phenomena across phyla for decades, mostly due to the ease of handling and sophisticated genetic manipulations with conserved cell signaling pathways of reduced redundancy. Considering a significant degree of homology in Drosophila for human disease-associated genes, it poses as a versatile in vivo platform to study the pathophysiology of various human diseases. With core metabolic pathways governing energy homeostasis generally conserved, Drosophila can be used as a model for studying molecular mechanisms underlying disease phenotypes manifested in obese and diabetic patients. In this review, we discuss representative Drosophila studies that investigated the effects of dysregulated core signaling pathways on metabolic signatures of obese animals.


Obesity , Type 2 diabetes , Drosophila Melanogaster , Signaling pathway

노랑초파리 동물 모델을 이용한 비만 연구

정 지은1),2), 이 주용4), 이 지혜1),2),3),4)*
1)부산대학교 치의학전문대학원 치의생명과학과
2)부산대학교 치의학전문대학원BK21 FOUR 사업단
3)부산대학교 치의학전문대학원 구강병리학교실
4)부산대학교 치의생명과학연구소

초록

    Ⅰ. INTRODUCTION

    All organisms have systems that recognize and absorb nutrients, which can be stored via appropriate metabolic processes and converted into usable forms of energy sources. Long-term intake of excess nutrients hinders metabolic homeostasis and induces the conversion of nutrients from nutrient utilization to nutrient preservation1). Such excess supply of nutrients leads to obesity, increasing the risk of cardiovascular diseases, cancers, and metabolic disorders, including diabetes mellitus (DM)2,3). Obesity refers to a state in which excess energy is stored as fat in the body. In general, the Body Mass Index (BMI) is used to determine whether an individual is overweight and obese. BMI score between 25 and 30 is defined as overweight, while the score over 30 is considered obese4). According to a recent report, the World Health Organization has estimated more than 1.9 billions people as being overweight in populations aged over 18, while nearly 650 millions were obese worldwide 5).

    There are multiple factors that contribute to development of obese states, including abnormal calorie intake, lack of physical exercise and genetic predispositions. For example, excessive uptake of calories can cause severe hypertrophic obesity6). In addition, incorrect eating habits such as regular food intakes at nighttime can cause obesity. During this time of day, the digestive system remains inactive, thus resulting in excessive energy storage. Therefore, people who prefer late-night snacks are more likely to become obese7). Furthermore, if lack of exercise is combined with development of insulin resistance, excess energy can easily turn into fat8). In addition to these environmental factors, genetic influences are evident in children with their parents in obese states. For instance, 24~28% of children become obese when either of their parents is in an obese state, while the rate only reaches 8~9% with non-obese parents9,10). Taken together, these findings indicate a complex nature of obesity that requires solid experimental validation of molecular mechanisms underlying its pathophysiology, often with alternative animal models. The majority of current studies on obesity rely upon the mouse model to understand the interaction between high-nutrient diets and development of obesity. In this review, we provide an overview of recently developed Drosophila-based models as well as currently available mouse models in investigating the mechanisms underlying the cellular and systemic changes occurring in obese populations.

    Ⅱ. ADIPOCYTE METABOLISM and INSULIN RESISTANCE

    Adipocyte metabolism plays a critical role in development of obesity. Adipocytes are divided into white fat cells for storing fat and brown fat cells for heat production11,12). Briefly, brown adipocytes act on postprandial heat production, thus contributing to the maintenance of body temperature in response to a temperature drop13,14). Indeed, OB mice, with abnormal brown adipocyte functions, are subject to death when exposed to a low temperature around 4°C15,16). Consistent with this result, the fraction of brown-adipocytes in the body of obese family members is lower than that of control population17). Additional abnormalities in β3 adrenergic receptor genes that regulate brown adipocyte function were found in obese animals, as well as in obese people with family history18). As a result, epinephrine increases heat generation in control population, but not in obese patients18).

    Recent studies have proposed categorization of obesity according to changes in the number and size of adipocytes 19). Three categories of fat cell changes are observed in obese populations: 1) hypertrophic obesity in which the number of fat cells remains unchanged, but their size increases, 2) proliferative obesity in which the number of fat cells increases with no change in their size, and 3) mixed obesity in which the number and size of fat cells are both increased. Obesity occurring in infancy or childhood is often proliferative, while obesity in middle-age groups tends to be hypertrophic. Importantly, when proliferative obesity in childhood remains untreated, it progresses to mixed and severe obesity in adults with both proliferative and hypertrophic characteristics. In such case, it is very difficult to treat obesity even when the size of fat cells returns to a normal state, as the number of fat cells remain increased 19,20).

    Abnormal fat metabolism is directly associated with altered cellular responses to insulin21,22). Insulin exerts its action by binding to a specific receptor expressed on the cell membrane of peripheral target cells23). These targets may develop insensitivity to the circulating insulin, i.e. “insulin resistance”, a state in which the blood glucose level remains abnormally high even in the presence of sufficient amount of circulating insulin8). In obese patients, glucose and lipid metabolism is abnormally regulated, resulting in hyperinsulinemia and subsequent insulin resistance. In addition, these populations may develop other metabolic abnormalities such as non-insulin-dependent DM or hyperlipidemia 24). In proliferative obesity that begins in childhood, the degree of hyperinsulinemia is relatively mild, but the degree of hyperinsulinemia and insulin resistance is remarkable in adult patients with hypertrophic obesity25). Such adult-prone obesity may involve a decrease in expression of surface insulin receptors as well as deregulation of intracellular metabolic signaling downstream of insulin receptors, both of which lead to more severe course of obesity 26).

    Persistent insulin resistance ultimately leads to development of DM. Diabetes is a syndrome consisting of chronic hyperglycemia and its long-term complications manifested in multiple body organs and systems. Diabetes is the third major chronic disease following cancer and cardiovascular disease that threatens human health27). The American Diabetes Society has categorized diabetes as type 1 diabetes (T1D), type 2 diabetes (T2D), and other types, including gestational diabetes. Among these categories, T2D accounting for about 90% of diabetics is a classical metabolic disease characterized with initial development of insulin resistance and subsequent loss of circulating insulin in the late stage28).

    Ⅲ. THE ANIMAL MODEL of OBESITY

    Animal models of metabolic diseases such as obesity and T2D can be generated by the compound administration, diet regulation and surgical intervention. Animal models are essential subjects of research to better understand the molecular mechanisms of obesity and to develop effective treatment remedies29). At present, obesity animal models are divided into four main types: dietary induction, hypothalamic injury, endocrine ataxia and hereditary predisposition30). In this review, we briefly overview two representative models of obesity, Mus musculus and Drosophila melanogaster.

    Obese mouse models

    Obese mouse models are often used to study the relationship between diets/genetic factors and obesity20) (Tables 1 and 2). These models are also suitable for studying preclinical efficacy of candidate drugs to treat obesity and T2D31,32). The function of pancreatic b-cells is relatively well maintained in some mouse models, while others display gradually deteriorating b-cell function as the disease progresses, similar to human T2D patients (Table 2). Obesity in mice can be induced by a high-fat diet or by an application of a drug such as Streptozotocin (STZ). These models are characterized with insulin resistance induced by a high-fat diet and with pancreatic beta cell dysfunction induced by STZ, similar to human diabetic conditions33). In spiny mice (Acomys cahirinus), high-fat diets can induce expansion of beta-cell populations, ultimately leading to their rupture and severe diabetes34). In addition, an administration of gold thioglucose in mice can induce hyperphagia and severe obesity, mostly due to the failure of pancreatic insulin secretion to compensate for tissue resistance35).

    In addition, insulin resistance in mice can also be induced by leptin deficiency due to recessive mutations in the LEP gene encoding leptin and by subsequent increases in cortisol levels36). Similarly, an autosomal recessive gene mutation in the leptin receptor gene, LEPR, can also induce insulin resistance37,38). Additional variations in Agouti gene also lead to development of obese characteristics, including hyperphagia, hyperinsulinemia, and glucose intolerance as well as yellow skin pigmentation (“Yellow obese mice”)39). In line with such skin pigmentation, New Zealand Obese (NZO) mice characterized with hypertension, obesity, mild hyperglycemia and high insulin resistance are selectively bred based on agouti coat color as a model of obesity and diabetes40). In addition, obesity and T2D can also be studied in polygenic models, such as KK (Kuo Kondo) and KK/Ay mice. These models are generated by selective inbreeding of large mice in Japan, with insulin resistance preceding obesity41). Interestingly, KK.Cg-Ay/J heterozygotes also exhibit hyperglycemia, hyperinsulinemia, glucose intolerance, and subsequent obesity within 8 weeks, and can be considered as a hybrid between the Ay heterozygote and Japanese KK mice42).

    Other rodent models for obesity and diabetes include a few rat models (Table 2). For instance, Zucker fatty rats (ZFR)43) and spontaneously hypertensive rat/NIH-corpulent (SHR/N-cp) rats44) show severe hyperinsulinemia and relatively mild hyperglycemia while maintaining beta-cell insulin secretion. In GK (Goto-Kakizaki) rats, T2D can be studied without extreme leptin deficiency or severe obesity 45).

    Drosophila melanogaster model

    Drosophila melanogaster has positioned itself as a representative platform to study virtually all fields of biology, from embryology to aging, since 1900s. The overall advantages of Drosophila melanogaster in studying human diseases include: 1) relatively small size of animals and ease of rearing, 2) large numbers of offspring per each reproduction cycle, 3) ease of genetic manipulations with sophisticated experimental tools and 4) simple genomic composition with significant degree of homology to human genome46,47). Briefly, about 75% of human disease-associated genes have orthologs or homologs in Drosophila genome. With core signaling pathways mostly conserved in Drosophila, they can serve as an effective model for understanding the functions of human disease-associated genes48). For instance, obesity-induced T2D can be successfully modeled in Drosophila, as insulin-like factors are secreted from a specific set of endocrine cells similar to human pancreatic beta cells49). Here we provide an overview of a few representative Drosophila models of obesity and diabetes.

    Drosophila embryos and larvae can be used for studying various cellular signals and relevant behaviors due to the ease of manipulation and the speed of rearing. Drosophila larvae exhibit functional networks that allow us to investigate genetic interactions, hormonal regulation and disease- related signaling activities observed in late adolescence 50). Similar to a high-sucrose diet in mammals, a large amount of sugars in diet can cause obesity, hyperglycemia and insulin resistance in Drosophila larvae, consistent with the pathophysiology of human T2D51). Along with hyperglycemia-associated fat accumulation, expression of FOXO targets and genes involved in adipogenesis and gluconeogenesis are upregulated in larvae fed with a high-sugar diet52).

    Similar approaches using diet induction can be applied to adult obesity models in flies. For instance, adult flies can be fed with high-sugar and/or high-fat diets to induce obesity. Such diet manipulation can develop insulin resistance, ultimately resulting in metabolic disorders such as diabetes and their complications, including cardiovascular diseases 53-55). These adult fly models also offer unique opportunities to study the effects of diet on multiple biological aspects of animals, including cellular metabolism, behaviors, aging and longevity56). The initial report from Southern Methodist University successfully demonstrated high-nutrient diet-induced insulin resistance in adult flies, a characteristic of T2D57). In this report, insulin-resistant Drosophila models were generated in two different ways: one group consumed too much carbohydrates, whereas the other group consumed too much protein. The carbohydrate group gained weight and accumulated fat, while the protein group initially gained weight but eventually lost weight with a protein-only diet. For insulin resistance, both groups developed the resistance, but with a faster and more severe degree in the protein group. In addition, both groups exhibited severely shortened lifespan compared to the controls 57). A recent study design using adult flies incorporated a modified paradigm of a high-fat diet by adding 10% and 20% coconut oil rich in saturated fat58). A 7-day-long high-fat diet resulted in altered expression of genes involved in metabolic and oxidative stress that may contribute to shortened life expectancy in Drosophila fed with a high-fat diet58).

    Signaling pathways implicated in obesity and diabetes in Drosophila models

    The molecular mechanisms underlying development of obesity and T2D in flies have been a focus of main stream research in the field over the last decades. The outcomes from these research efforts suggest a few core signaling pathways that play a critical role in the pathophysiology of obesity in flies, including insulin receptor-mediated signaling, AMPK pathways, PPAR-mediated signaling and chromatin correction pathways23) (Table 3).

    Insulin resistance can be induced in part by downregulation of insulin receptor. With reduced expression of insulin receptor and subsequent loss of insulin signals, interactions between the regulatory subunit (P85) of infinositide- 3 kinase (PI3K) and insulin receptor substrate protein IRS-1/2 are diminished, resulting in reduced activities of the downstream signaling59). Importantly, defects in insulin signal transmission in Drosophila lead to phenotypes similar to mammalian diabetes60). Drosophila insulin receptor (dInR) regulates various biological processes, including growth, axon induction, and sugar homeostasis. dInR-mediated growth regulation is mediated by Chico, a homolog of human IRS1-461). In addition, a recent report with adult fly models has identified a novel gene, Meep, in providing a protective property against high-sugar diets in an insulin receptor-dependent manner62).

    AMP-activated protein kinase (AMPK) plays a critical role in regulating cellular energy metabolism, by inactivating gluconeogenesis in the liver63). It also inhibits acetyl core carboxylase (ACC) and activates malonyl core carboxylase (MCD) to induce lipid metabolism64). Expression of AMPK-α /β/γ monomers in Drosophila allows a fine control over energy homeostasis, thus providing sufficient protection against neurodegeneration and reduced life expectancy65). A chemical intervention of AMPK activity using iron oxide nanoparticles demonstrated diminished hyperglycemia and hyperinsulinemia in Drosophila, thus confirming the role of AMPK pathway activity in glucose metabolism and insulin response66). Similarly, a dietary intake of epicatechin with enhanced AMPK activity was sufficient to increase mean lifespan of Drosophila, consistent with its protective effects in mice67).

    Peroxisome proliferator-activated receptors (PPARs) belong to a superfamily of ligand-activated transcription factors with three major subtypes, PPARα, PPARb/δ and PPARγ68). These PPARs expressed in various organs, such as the liver and muscles, mainly participate in glucose and lipid metabolism 68,69). Importantly, the agonists for PPARs are used for treating metabolic syndromes including hyperlipidemia, T2D and cardiovascular diseases68). Fatty acids can act as PPAR agonists, modulating lipid and energy metabolism in Drosophila. For instance, a knock-down of acetyl-Coenzyme A-carboxylase (ACC), a core enzyme for fatty acid synthesis, decreased triglyceride storage with a concurrent increase in glycogen storage in Drosophila fat body70). In addition, Drosophila Adipose gene in the enzymatic cascade of triglyceride synthesis inhibits fat accumulation by inactivating PPARγ via a recruitment of HDAC371). Overexpression of Adipose in Drosophila fat bodies caused a significant reduction in fat storage, thus confirming the critical role of PPAR signaling pathways in regulation of lipid metabolism72).

    Ⅳ. CONCLUSION

    The prevalence of metabolic diseases in the current aging society has continued to increase dramatically due to significant changes in life styles and environments, thus requiring fundamental and effective research on the prevention and treatment of these diseases73). Obesity is a complex chronic disease that progresses over decades with deteriorating physiological functions. To study the pathophysiology of obesity and related metabolic disorders such as diabetes, one can employ various animal models generated by genetic manipulation and environmental regulation according to a specific purpose of individual experiments. The mouse model of diet-induced obesity has become one of the most important tools to understand the interaction of high-fat diets and development of obesity. Meanwhile, the core signaling mechanism regulating metabolic homeostasis is highly conserved in both Drosophila and mammals. With the ease of rearing and genetic manipulations, Drosophila is an excellent model for studying metabolism-related human illnesses. Induction of insulin resistance, hyperglycemia and other T2D-like phenotypes emulated in Drosophila further confirms the value of Drosophila model in studying human obesity and related metabolic disorders 74). Therefore, a Drosophila model could pose itself as an attractive alternative model in deciphering the molecular mechanisms underlying the pathophysiology of obesity and in developing an innovative approach for disease treatment.

    ACKNOWLEDGMENTS

    This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (grant number 2021R1A6A3A13039383) and by BK21 FOUR Program by Pusan National University Research Grant, 2020 to Ji-Eun Jung.

    Figure

    Table

    Mouse models with obesity and diabetes

    Rodent models with phenotypic similarity to human type 2 diabetes

    Obesity-related signaling networks conserved in Drosophila

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