Narrative review of ferroptosis in obesity

Abstract Obesity is widely recognized as a major global health problem caused by a chronic energy imbalance resulting from a combination of excess caloric intake and insufficient energy expenditure. Excessive energy intake and physical inactivity are traditional risk factors for obesity. Obesity is a risk factor for many diseases, including hypertension, diabetes and tumours. Recent studies have found a strong link between ferroptosis and obesity. Ferroptosis is an iron‐dependent regulated cell death caused by iron overload and reactive oxygen species‐dependent excessive accumulation of lipid peroxidation. Ferroptosis is involved in many biological processes, such as amino acid metabolism, iron metabolism and lipid metabolism. Some potential strategies to reduce the adverse effects of ferroptosis on obesity are suggested and future research priorities are highlighted.


| INTRODUC TI ON
Obesity is a serious, chronic, complex and relapsing disease associated with changes in adipose tissue mass, distribution or function, which is associated with severe morbidity and increased mortality.
Obesity has become the world's largest chronic disease. According to the World Health Organization (WHO) 2017 Global Disease Report, an estimated 107.7 million children and 603.7 million adults were obese globally in 2015. The overall obesity rate is 5.0% and 12.0%, respectively, which is the country with the highest obesity rate in China. 1 Obesity is caused by the interaction of genetic, environmental, physiological, behavioural and sociocultural factors. 2 In general, obesity is caused by multiple factors that affect energy intake and expenditure. The main route of energy intake is through food intake or feeding behaviour. Feeding behaviour is regulated by the hungersatiety circuit in the central nervous system. The arcuate nucleus (ARC) of the hypothalamus is thought to be the primary site for integrating hunger-satiety circuit. ARC within the hypothalamus produces orexinergic neuropeptides agouti-related peptide (AgRP)/neuropeptide Y (NPY), proapipimelanocortin (POMC)/cocaine-and amphetamineregulated transcript (CART). Stimulation of AgRP/NPY neurons leads to increased food intake and weight gain. 3 However, lateral cells of the ARC release the POMC-derived peptide alpha-melanocyte-stimulating hormone (α-MSH) potently reduce food intake. 4 In addition to the central nervous system, energy intake and expenditure are also influenced by lifestyle. For example, there is a physiological link between sleep and energy balance. 5 Lack of sleep is a risk factor for overeating and weight gain, and molecules such as orexin and insulin play an important role in controlling sleep and energy intake. Lifestyle can also induce activation or inhibition of adenosine monophosphate-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) signalling pathway, which regulates the energy balance. 6 Thermogenesis is also a way of regulating energy balance. Brown adipose tissue (BAT) is rich in mitochondria containing uncoupling protein 1 (UCP1), which uses energy through thermogenesis. 7 Shiverless thermogenesis in skeletal muscle is also an attractive strategy to combat obesity. 8 The gut microbiota also affects host energy balance by regulating genes related to fat absorption and storage. Study found that noni fruit phenolic extract suppresses obesity by increasing short-chain fatty acid (SCFA)-producing bacteria and suppressing abnormalities in the gut microbiota. 9 In addition, glucagon-like peptide-1(GLP-1), incretins and pleiotrophins have pharmacotherapeutic potential in the treatment of obesity. 10 See Figure 1 for a brief summary of metabolic imbalance and obesity.
Ferroptosis is an iron-dependent regulated cell death (RCD) caused by iron overload and reactive oxygen species (ROS)dependent excessive accumulation of lipid peroxidation, first proposed by Dixon et al. 11 in 2012. Ferroptosis is characterized by changes in mitochondrial morphology, including mitochondrial shrinkage, reduced or absent mitochondrial cristae, and increased mitochondrial membrane density. 12 Its bioenergetic features are mainly iron accumulation and lipid peroxidation. 12 It has been established that ferroptosis is involved in the initiation and progression of many diseases. These diseases ( Figure 2) included stroke, 13  and nonalcoholic fatty liver disease. 31 Furthermore, ferroptosis is closely related to many disease processes, such as oxidative stress, 32 inflammatory response 33 and autophagy. 34 In particular, ferroptosis is involved in the pathological process of obesity. 35 Excessive nutrient intake and fat storage in white adipose tissue (WAT) ultimately leads to obesity. Insufficient iron intake is also linked to overweight or obesity in children and adolescents. 36 A systematic meta-analysis of 21 studies (including 13,393 overweight participants and 26,621 non-obese participants) found a significant association between obesity and iron deficiency. 37 Therefore, understanding the regulatory pathways of ferroptosis is of great significance for the prevention and treatment of obesity. Ferroptosis is involved in many biological processes, such as amino acid metabolism, iron metabolism, lipid metabolism ( Figure 3).

| The lipid metabolism in ferroptosis
It is known that when mammals cannot use carbohydrates to generate adenosine triphosphate (ATP), glucose is mostly converted into fatty acids (lipogenesis) for synthesis and storage of triglyceride (TGs) in the liver and white adipose tissue. Lipid droplets are universal storage organelles for neutral lipids (TGs) that can be found in most cells. Dynamics and functions of lipid droplets have been recently reviewed. 42 Lipid droplets showed that they were encapsulated by a factor called Fas-associated factor 1, which protected them from contact with Fe 2+ . 43

| The role of GSH/GPX4 pathway in ferroptosis
Glutathione (GSH) is a potent antioxidant that plays an important role in ferroptosis due to its ability to scavenge excess ROS. pathway, termed "Nrf2" activators; have received increasing attention for their potential as GSH enhancers. Glutathione peroxidase 4 (GPX4) converts reduced GSH to oxidized glutathione (GSSG) and reduces cytotoxic lipid peroxides. 44,45 All molecules involved in the regulation of the GSH/GPX4 axis can be potential targets for the regulation of ferroptosis.

F I G U R E 4 The lipid metabolism in ferroptosis.
known as mitochondrial apoptosis-inducing factor 2 (AIFM2). It was initially annotated as a p53-responsive gene, and later reports showed that it is highly homologous to apoptosis-inducing factor (AIF). [49][50][51] FSP1 is a member of the type II NADH: quinone oxidoreductase (NDH-2) family. So, its intrinsic role is to reduce CoQ10 using NADH. 52 Two important reports demonstrated the role of FSP1 as a novel suppressor of ferroptosis. 53,54 N-myristoylation of FSP1 mediates the recruitment of this protein to lipid droplets and plasma membranes. It is necessary and sufficient to confer resistance to ferroptosis. FSP1 is a membrane-recruited oxidoreductase that catalyses the transport of reduced NADH analogs of coenzyme Q10 into the lipid bilayer, thereby inhibiting lipid peroxidation. The ferroptosis inhibitor iFSP1 acts mainly by directly inhibiting FSP1. FIN56 can bind and activate squalene. 55 As an antioxidant pathway parallel to GSH/GPX4 pathway, CoQ10/FSP1 antioxidant pathway must also play an important role in ferroptosis.

| GCH1-BH4-phospholipid pathway in ferroptosis
The GCH1-BH4-phospholipid pathway also has an antioxidant effect on ferroptosis via CoQ10. Tetrahydrobiopterin (BH4) is a redoxactive cofactor for several key enzymes involved in the production of nitric oxide, neurotransmitters and aromatic amino acids 56,57 Guanosine triphosphate cyclohydrolase 1 (GCH1) is the rate-limiting enzyme of BH4 biosynthesis. BH4 may promote the synthesis of CoQ10 by converting phenylalanine into tyrosine that can be further converted to 4-OH-benzoate, a precursor of CoQ10. Besides, BH4 can directly protect two-tailed PUFA phosphatidylcholines from peroxidation to resist ferroptosis. This pathway is also a GPX4 -independent pathway ( Figure 3).

| Regulating iron metabolism in ferroptosis
Since iron is tightly regulated by controlling iron uptake, storage, utilization and efflux. Therefore, regulation of iron metabolic processes can inhibit ferroptosis. For example, it can regulate iron absorption.
Calcium is a noncompetitive inhibitor of iron importer divalent metal transporter 1 (DMT1) on the intestinal iron absorption. Vitamin D is known to promote calcium absorption. Study found that micronutrient (Vitamin D) deficiencies are common in obesity. 58 Obesity is a risk factor for diabetes, and people with diabetes may also be deficient in vitamin D. 59 Interventions consisting of calcium and iron may provide new ideas for obesity prevention.

| Regulating GPX4 pathway in ferroptosis
Modulating GPX4 activity and expression is also a potential strategy to alleviate ferroptosis. Silent information regulator factor 2-related enzyme 1 (SIRT1)/Nrf2/GPX4 signalling pathway as a potential therapeutic target for inhibiting ferroptosis. 60 SIRT1 is a nicotinamide adenine dinucleotide-dependent histone deacetylase, promote longevity and protect individual organisms from age-associated diseases. 61 In additional, sphingosine 1-phosphate (S1P) alleviates radiation-induced ferroptosis in ovarian granulosa cells by upregulating GPX4. Physical activity activates the SIRT1 pathway, 62 which has also been linked to creativity. 63 Physical activity can also indirectly regulate the activity and expression of GPX4. As mentioned above, GPX4 signalling pathway as a potential therapeutic target for inhibiting ferroptosis. Therefore, we speculate that the S1P signalling pathway may be an indirect regulatory target of ferroptosis. The effects of sphingolipid metabolism disorders on endothelial cells have been reviewed in detail elsewhere. 64  activity and expression is also a potential strategy to alleviate ferroptosis. Silent information regulator factor 2-related enzyme 1 (SIRT1)/Nrf2/GPX4 signalling pathway as a potential therapeutic target for inhibiting ferroptosis. S1P attenuates radiation-induced ferroptosis in ovarian granulosa cells through upregulation of GPX4. Therefore, we speculate that the S1P signalling pathway may be an indirect regulatory target of ferroptosis.

CO N FLI C T O F I NTE R E S T S TATE M E NT
The author confirms that there are no conflicts of interest.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data sharing not applicable to this article as no datasets were generated or analysed during the current study.