Background: Growth differentiation factor-15 (GDF15) is a member of the growth differentiation factor subfamily in the transforming growth factor beta superfamily. GDF15 has multiple functions and can regulate biological processes. High levels of GDF15 in the circulation can affect metabolic processes. Studies have shown that GDF15 is associated with changes in body weight. Summary: This review reviews the current knowledge on the relationship between GDF15 and body weight change, focusing on the role and mechanism of GDF15 in body weight regulation. GDF15 plays an important role in reducing food intake, improving insulin resistance, and breaking down fat, suggesting that GDF15 has an important regulatory effect on body weight. The mechanism by which GDF15 causes reduced food intake may be related to changes in food preference, delayed gastric emptying, and conditioned taste aversion. GDF15 can combat insulin resistance induced by inflammation or protect β cell from apoptosis. GDF15 probably promotes lipolysis through a brain-somatic tissue circuit. Several factors and related signaling pathways are also mentioned that can contribute to the effects of GDF15 on reducing weight. Key Message: GDF15 plays an important role in weight regulation and provides a new direction for the treatment of obesity. Its effects on resisting obesity are of great significance to inhibiting the progression of metabolic diseases. It is expected to become a new target for regulating body weight, improving obesity, and treating metabolic diseases such as diabetes.

Obesity is an inflammatory state caused by the accumulation of adipose tissue in the body, which can be regarded as a risk factor for some diseases. As a stress-responsive cytokine, growth differentiation factor-15 (GDF15) is expressed in multiple tissues and can be overexpressed after certain types of stimulation. GDF15 can reduce body weight, affect metabolic processes associated with obesity, and inhibit chronic low-grade inflammation caused by adipose tissue. This has led to GDF15 gaining widespread attention in combating obesity and related risk factors. The development of intervention drugs that modulate GDF15 or its signaling metabolic pathways may help treat obesity and related health conditions. In this review, we focus on three methods by which GDF15 regulates body weight: reducing appetite, improving systemic insulin resistance, and promoting lipolysis. In addition, we discuss factors that regulate GDF15 to reduce weight, aiming to find a novel type of treatment.

Introduction of GDF15

GDF15 is a transforming growth factor-b superfamily protein located on chromosome 19p13.11 [1]. Under physiological conditions, GDF15 mRNA is expressed in tissues such as the liver, lung, and kidney and is abundantly expressed in placental trophoblast cells [2]. As a stress response cytokine, GDF15 can increase its expression and secretion into the circulation under the conditions of aging, pregnancy, exercise, and fasting [3‒6]. GDF15 is also influenced by genetic factors. Among the SNPs near the 3′ untranslated region of the GDF15 locus, rs1054564 is significantly associated with circulating GDF15 levels [7]. It confers allele-specific translational repression of GDF15 via hsa-miR-1233-3p [8].

GDF15 has multiple functions and can regulate biological processes, such as inhibiting the secretion of TNF-α by macrophages, inducing cartilage formation and the early stages of endochondral bone formation, and promoting the apoptosis of tumor cells such as large intestine and breast cancer cells. This is why GDF15 has many other names, such as NSAID-activating gene 1 (NAG-1) [9], macrophage inhibitory cytokine 1 (MIC-1) [1], and prostate-derived factor (PDF) [10]. Under pathological conditions, the serum level of GDF15 can increase in tumors, diabetes, cardiovascular diseases, mitochondrial damage, and other diseases [11‒14].

In addition to glucose metabolism and lipid metabolism described in detail below, GDF15 can affect ion metabolism and iron metabolism pathways. GDF15 can mediate proliferative effect on type A intercalated cells through the ErbB2 receptor in the presence of type 2 H,K-ATPase and maintain K+ balance [15]. Hepcidin maintains systemic iron homeostasis, and GDF15 has been shown to regulate iron metabolism by inhibiting hepcidin expression in primary hepatocytes [16]. GDF15 has also become an important factor affecting iron metabolism in certain diseases such as hepatocellular carcinoma and erythroid diseases [17, 18]. These findings demonstrate the important regulatory role of GDF15 on body metabolism.

GDF15 has been widely studied in the field of tumors. Johnen et al. [19] found that tumor-bearing mice overexpressing GDF15 exhibit a sharp drop in body weight. The content of GDF15 can be 40,000 pg/mL. In contrast, the use of GDF15 antibody can reverse weight loss, suggesting a role for GDF15 in weight reduction in cancer.

The Association between GDF15 and Weight Change

Under physiological and pathological conditions, the level of GDF15 is related to changes in body weight. In newborns, the concentration of GDF15 decreases at approximately 4 months, and circulating GDF15 levels correlate inversely with changes in body fat. Growth-promoting insulin-like growth factor-1 and early adipogenesis-promoting high molecular weight adiponectin also increase, suggesting that decreases in GDF15 can increase weight [20]. This change is more pronounced in lighter weight preterm infants, indicating that lower GDF15 levels may be an adaptive mechanism to promote catch-up in weight.

Human genetic studies have mentioned the relationship between GDF15 and obesity. A genome-wide association study of up to 339,224 individuals focused on BMI and identified 97 BMI-related loci, one of which was related to GDF15. Two genome-wide association studies, each involving approximately 700,000 participants, demonstrated that the GDF15 intronic variant rs10424912 and downstream variant rs16982345 are associated with BMI.

For epidemiological studies on the relationship between GDF15 and body weight, there are few large-scale clinical trials, and some studies with small sample sizes support the effect of GDF15 on reducing body weight. You et al. [21] selected 203 volunteers and found by logistic regression analysis that high levels of GDF15 were associated with an odds ratio of BMI of 0.75 (p < 0.02), indicating that people with high levels of GDF15 usually have low BMI levels. In patients with severe obesity who underwent Roux-en-Y gastric bypass (RYGB) surgery, GDF15 levels were elevated after surgery [22], and the level of measured weight loss was positively correlated with GDF15 [23]. These studies indicate that elevated GDF15 levels can reduce body weight to combat obesity from a clinical perspective.

GDF15 plays an important role in combating obesity. GDF15 may be involved in appetite control and energy expenditure to reduce body weight. Tsai et al. [24] administered recombinant GDF15 (rGDF15) to obese mice and observed weight loss in the mice. Regardless of whether the mice were fed a normal chow diet (NCD) or a high-fat diet (HFD), reduced energy expenditure and increased food intake occurred in the mice and caused obesity [25, 26]. A reduced exercise capacity also occurs in GDF15 KO mice fed a HFD, indicating that loss of GDF15 exacerbates the development of obesity.

GDF15 has been linked to several metabolic processes associated with obesity, such as improving insulin sensitivity and reducing fat accumulation. In ob/ob mice, the administration of rGDF15 decreased body weight and improved insulin sensitivity, which was attributed to elevated oxidative metabolism and lipid mobilization in the liver, muscle, and adipose tissue [27]. The administration of rGDF15 to obese mice reduces body fat [24]. The opposite results were seen after administration of the GDF15 antibody, with mice fed a HFD having increased mean fat mass, hepatic lipid deposition, and impaired glucose tolerance [28]. It is suggested that GDF15 may combat obesity by improving glucose tolerance, improving insulin resistance and promoting lipolysis.

GDF15 has been found to have anti-inflammatory properties and can help suppress inflammation in various tissues. A GTEx RNAseq data analysis indicated that GDF15 gene expression positively correlates with the expression of inflammation-related genes in the liver, adipose tissue, and skeletal muscle from humans. Overexpression of GDF15 or administration of rGDF15 in obese mice can reduce inflammatory markers in serum and white adipose tissue (WAT) [24, 29]. This reflects the anti-inflammatory effect of GDF15. Tsai et al. [28] used an anti-human GDF15 antibody to treat Gdf15hu+/+ mice expressing human GDF15. After 97 days, the body weight of the mice increased by 17.6 ± 1.5 g on average. RNA expression of the major proinflammatory cytokines was significantly increased. This shows that inhibition of GDF15 function in mice will cause an increase in adipose tissue inflammatory markers and weight gain. At the same time, insulin resistance was also observed, suggesting that GDF15 inhibits insulin resistance by reducing inflammation.

GDF15 has been considered a potential biomarker for assessing obesity and obesity-related risks [30, 31]. Johnen et al. [32] observed that after 6 months of a HFD, ApoE(−/−) mice overexpressing GDF15 had smaller atherosclerotic lesions. The protective effect of GDF15 on the cardiovascular system has also been confirmed by many studies [33, 34]. These findings suggest that GDF15 may help counteract some of the detrimental effects of obesity on the cardiovascular system. These studies confirm that GDF15 can inhibit obesity, and GDF15 has been considered a potential target for the clinical treatment of obesity.

GDF15 Reduces Food Intake

In the past, GDF15 was called “limosin” [35], a kind of anorexic factor. GDF15 can reduce weight by suppressing food intake. Day et al. [36, 37] used metformin to promote GDF15 secretion in mice on a HFD and found that the food intake of mice was lower than that of the control group. This change disappeared in GDF15 knockout mice, indicating that elevated GDF15 levels inhibit food intake. This effect is mediated by the binding of GDF15 and its receptor, glial cell-derived neurotrophic factor receptor alpha-like (GFRAL). GFRAL belongs to the glial cell-derived neurotrophic factor receptor family. It is highly concentrated in the area postrema and nucleus tractus solitarius (NTS) in the hindbrain, which is the center that induces vomiting or emetic-like behaviors such as nausea and discomfort. After GDF15 specifically binds to GFRAL, the complex induces activation and phosphorylation of the signaling coreceptor Ret to activate the signaling molecules Akt, Erk, and PLCγ, which have anorexic effects [38‒41] (shown in Fig. 1). Silencing PBN neurons expressing calcitonin gene-related peptide abrogated the anorectic effect of GDF15 [42], indicating that this neuron mediates the anorectic effect of GDF15. Worth et al. [43] found that GFRAL is localized on cholecystokinin (CCK)-positive neurons, GDF15 can activate CCK neurons, and GDF15-induced anorexia can be attenuated by CCK signal blockade, indicating that GDF15 can be mediated by brainstem CCK neuron anorexia signals. The exact mechanism by which GDF15 causes reduced food intake remains to be elucidated and may be related to changes in food preference, delayed gastric emptying, and conditioned taste aversion (CTA) [34] (shown in Table 1; Fig. 1).

Fig. 1.

GDF15 specifically binds to GFRAL, and the complex induces activation and phosphorylation of the signaling coreceptor Ret to activate the signaling molecules Akt, Erk, and PLCγ. GDF15 causes reduced food intake which may be related to changes in food preference, delayed gastric emptying, and CTA. GDF15 can combat insulin resistance induced by inflammation or protect β cell from apoptosis. GDF15 probably promotes lipolysis through a brain-somatic tissue circuit. More signaling pathways of GDF15 regulating body weight remain to be elucidated.

Fig. 1.

GDF15 specifically binds to GFRAL, and the complex induces activation and phosphorylation of the signaling coreceptor Ret to activate the signaling molecules Akt, Erk, and PLCγ. GDF15 causes reduced food intake which may be related to changes in food preference, delayed gastric emptying, and CTA. GDF15 can combat insulin resistance induced by inflammation or protect β cell from apoptosis. GDF15 probably promotes lipolysis through a brain-somatic tissue circuit. More signaling pathways of GDF15 regulating body weight remain to be elucidated.

Close modal
Table. 1.

Influence of GDF on food intake, insulin resistance, lipolysis, and body weight under different conditions

Effect on GDF15ConditionsFood intakeInsulin resistanceLipolysisBody weight
Enhanced GDF15 overexpression Food intake↓ Insulin resistance↓ Fat accumulation↓ Body weight↓ 
rGDF15 
In NCD-fed mice [19, 26, 44In HFD-fed mice [27, 29, 47, 51In HFD-fed mice [41, 51, 52In NCD-fed mice [19, 26, 44
In HFD-fed mice [45‒48In obese cynomolgus monkeys [40, 49In HFD-fed mice [45‒47
In obese mouse models [24, 49In obese mouse models [24, 49
In obese cynomolgus monkeys [40, 49
In obese cynomolgus monkeys [40, 49
In shrews [50In shrews [50
External factors (drugs/surgery/exercise) Food intake↓ Insulin resistance↓ Fat accumulation↓ Body weight↓ 
In HFD-fed mice [36, 37, 53In HFD-fed mice [36, 37, 53In HFD-fed mice [37, 53In HFD-fed mice [36, 37, 53
In patients with severe obesity [54
Patient with diabetes and severe obesity [22, 23
Reduced GDF15-knockout or anti-GDF15 antibody Eliminates the reduced food intake Insulin resistance↑ In HFD-fed mice [48Eliminates the reduced food intake 
In NCD-fed mice [26, 28In NCD-fed mice [39‒41In HFD-fed mice lacking β adrenergic receptors [56In NCD-fed mice [26, 28
In HFD-fed mice [36, 37, 53
In HFD-fed mice [25, 28
In HFD-fed mice [36, 37, 53
 In mice under sleeve gastrectomy [55
GFRAL-knockout or anti-GFRAL antibody Eliminates the reduced food intake Eliminates the reduced food intake 
In NCD-fed mice [44, 45
In NCD-fed mice [44, 45
In HFD-fed mice [28, 39, 41, 45, 48
In HFD-fed mice [39, 41, 45, 48
No effect on HFD-fed mice [38
No effect on HFD-fed mice [38
Effect on GDF15ConditionsFood intakeInsulin resistanceLipolysisBody weight
Enhanced GDF15 overexpression Food intake↓ Insulin resistance↓ Fat accumulation↓ Body weight↓ 
rGDF15 
In NCD-fed mice [19, 26, 44In HFD-fed mice [27, 29, 47, 51In HFD-fed mice [41, 51, 52In NCD-fed mice [19, 26, 44
In HFD-fed mice [45‒48In obese cynomolgus monkeys [40, 49In HFD-fed mice [45‒47
In obese mouse models [24, 49In obese mouse models [24, 49
In obese cynomolgus monkeys [40, 49
In obese cynomolgus monkeys [40, 49
In shrews [50In shrews [50
External factors (drugs/surgery/exercise) Food intake↓ Insulin resistance↓ Fat accumulation↓ Body weight↓ 
In HFD-fed mice [36, 37, 53In HFD-fed mice [36, 37, 53In HFD-fed mice [37, 53In HFD-fed mice [36, 37, 53
In patients with severe obesity [54
Patient with diabetes and severe obesity [22, 23
Reduced GDF15-knockout or anti-GDF15 antibody Eliminates the reduced food intake Insulin resistance↑ In HFD-fed mice [48Eliminates the reduced food intake 
In NCD-fed mice [26, 28In NCD-fed mice [39‒41In HFD-fed mice lacking β adrenergic receptors [56In NCD-fed mice [26, 28
In HFD-fed mice [36, 37, 53
In HFD-fed mice [25, 28
In HFD-fed mice [36, 37, 53
 In mice under sleeve gastrectomy [55
GFRAL-knockout or anti-GFRAL antibody Eliminates the reduced food intake Eliminates the reduced food intake 
In NCD-fed mice [44, 45
In NCD-fed mice [44, 45
In HFD-fed mice [28, 39, 41, 45, 48
In HFD-fed mice [39, 41, 45, 48
No effect on HFD-fed mice [38
No effect on HFD-fed mice [38

↑, increase; ↓, decrease; GDF15, growth differentiation factor-15; GFRAL, glial cell-derived neurotrophic factor family receptor alpha-like; HFD, high-fat diet; NCD, normal chow diet.

After GFRAL knockout, the body weight of mice on a HFD was higher than that of wild-type mice; however, this change did not appear in mice on a normal diet [41], suggesting that GDF15 may inhibit the weight gain induced by a HFD. Xiong et al. [49] found that rhGDF15 reduced the mouse preference for a HFD. This is similar to Miyake’s findings. HFD-fed mice injected with rhGDF15 had higher food intake and weight loss than NCD-fed mice, and GDF15-treated mice preferred the NCD when they had free access to both diets. The preference disappeared after removal of GFRAL [45], indicating that GDF15 can reduce the mouse preference for a HFD and can reduce body weight. Further studies found that mice treated orally with medium-chain fatty acids increased GDF15 expression and reduced food intake. The change was attenuated in GFRAL-deficient mice. No changes were seen in mice that were orally administered long-chain fatty acids [44], indicating that the production of medium-chain fatty acids in a HFD setting may be a factor that promotes the increase in GDF15 and suppresses food intake.

GDF15 can also reduce food intake by delaying gastric emptying. This change disappeared after bilateral subdiaphragmatic vagotomy [49]. GDF15 can still inhibit food intake in rats when the selective vagal deafferentation technique is used [32]. This finding indicates that GDF15 delays gastric emptying only through the vagal efferent nerve. Borner et al. [57] found that the effect of delayed gastric emptying significantly differed only after high-concentration GDF15 treatment, suggesting that this effect requires high concentrations of GDF15 to work. However, GDF15 was used in combination with stimulating the release of satiety signals in the gastrointestinal tract of rats. It was found that the combined use of the two did not have a synergistic effect on reducing food intake [58], suggesting that GDF15 did not reduce food intake by increasing satiety.

Notably, the action of GDF15 in triggering vomiting and causing anorexia is similar to that of CTA. Patel et al. [46] found that a sharp increase in plasma GDF15 after subcutaneous injection of GDF15 can lead to a decrease in food intake. These mice behaved like the positive CTA control. Artificial activation of GFRAL-expressing neurons promotes CTA and inhibits food intake [42]. When GDF15 was present at the same time as food, it could significantly reduce the intake of this kind of food and change the emotional state of mice toward food from enjoyment to aversion [57], suggesting that GDF15 can reduce body weight by inducing CTA. In addition, Borner et al. [50] detected c-Fos protein in the NTS in vomiting animals after an injection of GDF15. This result indicates that GDF15 triggers vomiting by acting on the nucleus of the NTS, which may be the cause of CTA.

GDF15 Improves Insulin Resistance

In patients with insulin resistance, body compensation increases the secretion of insulin and exacerbates obesity. Obesity also exacerbates insulin resistance and impairs glucose and insulin tolerance [47]. GDF15 can combat obesity by reversing insulin resistance. Mice overexpressing GDF15 exhibit improved glucose tolerance and insulin sensitivity and reduced insulin levels and insulin resistance [59], which disappear after GDF15 knockout [25, 60]. Lu et al. [52] also induced the expression of GDF15 by camptothecin to increase glucose tolerance. Neutralizing GDF15 with an antibody abolished this effect, suggesting that GDF15 can improve insulin sensitivity and reverse insulin resistance. GDF15 depletion does not cause significant changes in body weight in 10- to 40- or 100-week-old mice, whereas 20-month-old mice develop significantly impaired glucose tolerance and insulin resistance [61], suggesting that the effect of GDF15 on systemic glucose homeostasis is related to age and that GDF15 protects against aging-induced insulin resistance. The mRNA expression of genes related to the insulin signaling pathway such as Irs1, Glut4, Akt, Pi3k, and As160 in mice overexpressing GDF15 was upregulated [51]. It indicates that GDF15 can activate the IRS1/AKT/PI3K signaling pathway to improve glucose metabolism and attenuate insulin resistance (shown in Fig. 1).

GDF15 may combat insulin resistance induced by inflammation. The mRNA expression level of caspase-1 in the WAT of mice overexpressing GDF15 was significantly reduced by 48% [29]. The expression of apoptosis-related speck-like protein, a key component of the NLRP3 inflammasome that activates caspase-1, was decreased, suggesting that GDF15 reduces the activity of the NLRP3 inflammasome by reducing the expression of key components such as ASC and then improves insulin sensitivity. Jung et al. [62] found that CR6-interacting factor 1-deficient mice had an increased proportion of CD45+ macrophages in adipose tissue and that oxidative function was impaired. This finding indicated that the reduced oxidative function of macrophages could lead to systemic insulin resistance and adipose tissue infiltration. After treatment with rGDF15 in these mice, the proportion of M1-type macrophages in WAT decreased, and the proportion of M2-type macrophages increased from 23.43 ± 3.72% to 30.40 ± 33.35%. The insulin resistance index of mice decreased, suggesting that GDF15 could improve glucose tolerance and reverse insulin resistance in mice, which may be achieved by regulating the polarity of macrophages in adipose tissue. In addition, rGDF15 in macrophages regulates macrophage polarity by stimulating the phosphorylation of SMAD2 and SMAD3 to transmit signals. This process can be abolished by SB431542, a selective inhibitor of TGF-βRI receptor kinases ALK4, ALK5, and ALK7. This response indicates that GDF15 transmits SMAD2 and SMAD3 activation signals through TGF-βRI receptor kinases ALK4, ALK5, and ALK7 and enhances the oxidative function of macrophages (shown in Fig. 1).

GDF15 has a protective effect on pancreatic beta cells. A cohort study on 160 participants with obesity found that β-cell function was positively correlated with GDF15 levels, suggesting that measurement of the GDF15 concentration can predict β-cell function in patients with severe obesity. Nakayasu et al. [63] pretreated insulin-producing cells with rGDF15 for 12–16 h and then treated them with IFN-g and IL-1b and found that caspase-3, which predicts apoptosis, was reduced by 50%. This result suggests that GDF15 can block islet cell apoptosis caused by proinflammatory cytokines and reduce insulin resistance. GDF15 can also directly increase glucose-stimulated insulin secretion. Zhang observed that administration of rGDF15 increased glucose-stimulated insulin secretion from pancreatic β cells. Similar changes were also produced in GFRAL-deficient mice [56]. This indicates that GDF15 can increase glucose-stimulated insulin secretion independent of GFRAL (shown in Table 1).

GDF15 Promotes Lipolysis

GDF15 can promote lipolysis to reduce weight. Zhang et al. [54] conducted an aerobic exercise intervention on 24 sedentary patients with severe obesity and found that plasma GDF15 increased after the intervention, and the amount of change in GDF15 was correlated with the reduction in total fat mass. Transgenic mice expressing human GDF15 or oral camptothecin-induced mouse GDF15 expression showed similar results [52], possibly due to increased expression of lipolytic genes in adipose tissue to prevent HFD-induced obesity. Zhang et al. [6] found that in mice with high levels of GDF15 in the liver, the expression of genes related to fatty acid β-oxidation and ketosis, such as Ppara, Pgc1a, Cpt1a, Acox, Cpt1a, and Hmgcs2, was dramatically upregulated. The levels of these genes were reduced after suppression of hepatic GDF15 expression. The mRNA levels of genes related to the production of new lipids in the liver, free fatty acid uptake, and very low-density lipoprotein secretion will not change, indicating that the increase in GDF15 levels promotes only the breakdown of lipids without affecting the synthesis and uptake of lipids [6].

Laurens et al. [64] subjected the primary myotubes of healthy volunteers to electrical impulse stimulation (EPS) to mimic the contraction of skeletal muscle under exercise. Lipolysis in the culture medium increased when EPS-stimulated myotubes were cocultured with human pluripotent adipose stem cells. Proteomic screening of EPS-stimulated myotubes showed that the level of GDF15 was upregulated by approximately 10-fold, suggesting that GDF15 is an exercise-regulating factor that promotes lipolysis. Levels of GDF15 secretion are different under the two exercise modes, as are energy metabolism pathways. Moreover, the lipolytic reaction in EPS24h medium can also be completely eliminated by neutralizing the IgG antibody of hGDF15, confirming that exercise makes skeletal muscle contract and can secrete GDF15 to decompose lipids, thereby reducing body weight. In addition, Suriben et al. [65] found that the expression of adipose triglyceride lipase (ATGL) in the WAT of wild-type mice was induced by GDF15, and this phenomenon disappeared in GFRAL knockout mice. Expression of GDF15 in the livers of ATGL knockout mice failed to reduce body weight or fat mass, suggesting that GDF15 can induce ATGL expression for lipid oxidation.

There may be human-specific targets for the lipolysis of GDF15. Laurens et al. [64] found that the GDF15 receptor GFRAL in adult female mice was detected only in the brain, while in human abdominal adipose tissue biopsy samples, the receptor GFRAL was found in the preadipose tissue. Emmerson et al. [41] also observed that human subcutaneous adipose tissue is the expression site of GFRAL, which reflects that human GDF15 also plays a role in adipose tissue and is different from that of mice. The GDF15 antibody can completely eliminate the lipolysis of abdominal fat explants caused by GDF15, indicating that in humans, GDF15 can not only act on the brain to cause anorexia but also target subcutaneous adipose tissue to promote lipolysis. Wang et al. [48] observed that β-less mice lacking β1, β2, and β3 adrenergic receptors were resistant to the effects of GDF15 to increase fatty acid oxidation. Chronic treatment of β-less mice with GDF15 did not reduce body mass. It indicates that GDF15 promotes lipolysis through a GFRAL-β-adrenergic signaling axis (shown in Table 1; Fig. 1).

Factors That Regulate GDF15 to Reduce Weight

Integrated Stress Response

The integrated stress response (ISR) is an adaptive response to stress in the endoplasmic reticulum and cytoplasm when the cell synthesizes abnormally expressed proteins. It transmits signals through the three transmembrane proteins IER1, ATF6, and PERK. Factors that cause changes in cell homeostasis, such as cold and mitochondrial diseases, can trigger the ISR [66, 67].

Patel et al. [46] treated mouse embryonic fibroblasts with different ISR inducers and found that the expression of GDF15 in the cells was increased. When the key transcriptional regulator of ISR activating transcription factor 4 or C/EBP-homologous protein (CHOP) was reduced or inhibitors of the PERK or EIF2α signaling pathway were used, the expression of GDF15 decreased, indicating that the ISR can promote the production of GDF15. Flicker et al. [66] observed that cold can activate activating transcription factor 4-dependent ISR in mouse brown fat, and after 6 h of cold exposure in mice, circulating GDF15 levels increased from 100 pg/mL to 200 pg/mL. GDF15 can upregulate the expression of β-oxidative genes in fat to promote lipolysis, suggesting that cold can activate the ISR to promote GDF15 expression, break down fat, produce heat, and reduce body weight.

Unfolded Protein Response

Excessive accumulation of misfolded proteins in the endoplasmic reticulum or mitochondria can cause the unfolded protein response (UPR), which can be coupled with ISR [68]. Under physiological conditions, exercise, fasting, or ketogenic diets [6, 69] can cause the UPR. Under pathological conditions, mitochondrial diseases caused by excessive accumulation of fat or mitochondrial oxidative phosphorylation dysfunction can also cause this response [6, 59, 60].

Choi et al. [59] observed that in AdKO mice with activation of the mitochondrial UPR, the relative expression of GDF15 in adipose tissue under a HFD was 10 times greater than that in the control group, and these mice exhibited higher glucose tolerance and insulin sensitivity. The adiponectin content that promotes fat synthesis was also reduced from 6,000 ng/mL to below 2,000 ng/mL. This suggests that the UPR can express GDF15, resist obesity, and reduce body weight.

Notably, Ost et al. [60] found that in TG mice with mitochondrial UPR caused by impaired skeletal muscle mitochondrial function, the plasma concentration of GDF15 increased, and the reduced food intake during the day resulted in lower energy intake than that of wild-type mice. This phenomenon disappeared in GDF15 knockout TG mice, suggesting that the mitochondrial UPR promotes GDF15 expression and inhibits mouse food intake during the day. There was no significant difference in the three groups of mice at night, and the 24-h energy intake was in the order of TG mice, wild-type mice, and knockout TG mice, suggesting that there may be diurnal differences in the effect of GDF15 on appetite suppression and weight reduction. Further research found that the circulating level of GDF15 in TG mice during the day was ≥400 pg/mL, while it decreased to below 400 pg/mL at night, indicating that the difference in the circulating level of GDF15 during the day and night affects the effect of inhibiting food intake, and the reason for this difference remains to be studied.

The expression of GDF15 may be related to the UPR signal transduction pathway of IRE1α-X-box binding protein (XBP1). Zhang et al. [6] injected an adenovirus that overexpressed XBP1 into mice and found that the mRNA level of GDF15 increased significantly, suggesting that XBP1 can promote the expression of GDF15. In subsequent chromatin immunoprecipitation assays, the labeled XBP1s and GDF15 promoter DNA were coimmunoprecipitated, and after knocking out the GDF15 and XBP1s potential binding site gene sequences, the transcriptional activity of GDF15 almost disappeared when XBP1 was overexpressed. This indicates that XBP1s can directly bind to the GDF15 promoter to activate GDF15 transcription.

The expression of GDF15 is also related to PERK-CHOP, another signaling pathway of the UPR. CHOP is involved in regulating GDF15 expression in human fibroblast lines. Li et al. [70] overexpressed CHOP with adenovirus and found that the abundance of GDF15 mRNA increased. Chromatin immunoprecipitation analysis also found that CHOP can bind to the GDF15 promoter, suggesting that GDF15 is a direct downstream target of CHOP. This is consistent with Lhomme’s findings that saturated fatty acids can induce endoplasmic reticulum stress to promote GDF15 expression through the PERK/eIF2/CHOP signaling pathway [71]. That is, the binding of endogenous CHOP generated by cellular stress to the GDF15 promoter also promotes GDF15 expression, reducing one of the mechanisms of body weight.

Continuous High-Calorie Diet

A sustained high-calorie diet can cause an increase in GDF15 levels. Under continuous HFD feeding, mice lacking GDF15 are more obese than wild-type mice. The glucose level of the mice rose significantly in the 4th week. From the 8th week, the GDF15 level of the mice rose significantly. Patel et al. [46] found that under a HFD, the fat and liver weights of mice fed continuously for 7 days increased, but the GDF15 level did not change significantly. This result may be because the short-term high-calorie diet did not destroy energy metabolism homeostasis; that is, to a certain extent, the high-calorie diet will not promote GDF15 production. These data reveal that continuous high-calorie feeding will increase the level of GDF15 to resist obesity, while short-term high-calorie feeding will not increase GDF15.

Drugs

Drugs such as metformin can also increase the expression of GDF15 and reduce body weight. Apolzan et al. [72] treated 3,234 random participants with metformin, lifestyle intervention, or placebo and screened 1,066 participants who lost more than 5% of their body weight within 1 year. During the following 6–15 years, the weight loss of subjects taking metformin was the most significant, indicating that metformin has a good weight reduction effect and is effective in preventing obesity and type 2 diabetes. In another study, 995 type 2 diabetes patients were treated with semaglutide, and 410 patients were treated with empagliflozin. The combination of metformin and semaglutide or empagliflozin can better treat patients with poorly controlled type 2 diabetes, and semaglutide 1 mg once a week can better reduce glycosylated hemoglobin and body weight [73]. Coll et al. [37] administered metformin orally to mice that were fed a HFD and found that metformin could induce an increase in GDF15 levels. The weight of the mice stopped increasing, and the weight loss effect of metformin in GDF−/− mice could not express GDF15. Insensitive mice lacking the GDF15 receptor GFRAL also expressed the same results. This suggests that metformin can promote an increase in GDF15 levels and reduce body weight. The cumulative food intake of mice on a HFD with oral metformin decreased. Indirect calorimetry showed that the metabolic rate of mice increased. These changes can be blocked by anti-GFRAL receptor antibodies, indicating that metformin inhibited mouse food intake and that increased energy consumption reduced weight.

Guillaume et al. [53] treated mice with tamoxifen (TAM), a selective estrogen receptor modulator of hepatocyte estrogen receptor alpha (ERα), and observed that the weight of the mice was reduced compared to that of the control group and that glucose tolerance and insulin resistance were improved. This reflects the improvement effect of TAM on insulin resistance and the effect on weight reduction. At the same time, the mRNA expression of GDF15 in the liver increased 8-fold. The above effect disappeared in GDF15 gene knockout mice, suggesting that the effect of TAM on improving insulin resistance and preventing obesity is achieved by promoting the secretion of GDF15. The effects are also completely eliminated in LERKO mice with hepatocyte-specific ERα deficiency. This result indicates that hepatocyte ERα mediates the regulation of GDF15 by TAM and the obesity resistance effect and that ERα has also become a potential target for upregulating GDF15 against obesity.

Gastric Surgery

Some operations, such as RYGB and sleeve gastrectomy, can significantly reduce the weight of patients with severe obesity. Both operations are also used in patients with severe obesity and diabetes. Kleinert et al. [22] performed RYGB on 22 diabetic people with obesity, and Dolo et al. [23] performed sleeve gastrectomy on 6 diabetic people with obesity. After surgery, the GDF15 levels of the patients were increased both several weeks and 1 year later, regardless of which operation was performed. The decrease in body weight is related to the increase in GDF15, suggesting that the increase in GDF15 levels may be one of the mechanisms by which both operations reduce the weight of patients with severe obesity.

However, in terms of the difference in the degree of GDF15 change between the people with obesity group and the people with diabetes and obesity group after surgery, the results between the two study groups were different. There was no significant difference between the two groups in RYGB surgery, while the diabetes with obesity group had a larger increase in GDF15 during sleeve gastrectomy. On the one hand, this may be due to the small sample sizes of both studies. On the other hand, the preoperative GDF15 level and age of the subjects in the two studies were different, which ultimately affected the results. Frikke-Schmidt et al. [55] found that in mice lacking GDF15, food intake and body weight were not changed after sleeve gastrectomy, suggesting that GDF15 is not a necessary factor for weight loss caused by bariatric surgery, and its specific mechanism remains to be studied.

Obesity is not uncommon clinically. Most patients living with diabetes, cardiovascular disease, and tumors have increased disease risk factors due to obesity. In recent years, there have been a multitude of studies on the contribution of GDF15 to weight control. GDF15 has attracted attention in the fight against obesity due to its role in reducing weight, affecting metabolism in the body, and inhibiting inflammation. GDF15 can reduce weight, mainly by suppressing appetite, improving insulin resistance, or promoting lipolysis. This also shows the role of GDF15 in resisting obesity. The level of GDF15 can be increased by internal factors such as the cellular stress response and external factors such as drugs, a continuous high-calorie diet, and gastric surgery to reduce weight. Overall, GDF15 is expected to become a new target for regulating body weight, improving obesity, and treating metabolic diseases such as diabetes. This review also provides a basis for GDF15 as a clinical treatment drug.

We declare that we have no financial or personal relationships with other people or organizations that could inappropriately influence our work. There is no professional or other personal interest of any nature or kind in any product, service, and/or company that could be construed as influencing the position presented in, or the review of, the manuscript titled “Research progress on the role and mechanism of GDF15 in body weight regulation.”

This work was supported by the National Nature Science Foundation of China (No. 82172550, 81871858).

Xiao-Chen Dong contributed to collecting the data and writing the manuscript. Dan-Yan Xu contributed to reviewing and editing the manuscript.

1.
Bootcov
MR
,
Bauskin
AR
,
Valenzuela
SM
,
Moore
AG
,
Bansal
M
,
He
XY
.
MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-β; superfamily
.
Proc Natl Acad Sci U S A
.
1997
;
94
(
21
):
11514
9
.
2.
Fairlie
WD
,
Moore
AG
,
Bauskin
AR
,
Russell
PK
,
Zhang
HP
,
Breit
SN
.
MIC-1 is a novel TGF-β superfamily cytokine associated with macrophage activation
.
J Leukoc Biol
.
1999
;
65
(
1
):
2
5
.
3.
Schafer
MJ
,
Zhang
X
,
Kumar
A
,
Atkinson
EJ
,
Zhu
Y
,
Jachim
S
.
The senescence-associated secretome as an indicator of age and medical risk
.
JCI Insight
.
2020
;
5
(
12
):
e133668
.
4.
Moore
AG
,
Brown
DA
,
Fairlie
WD
,
Bauskin
AR
,
Brown
PK
,
Munier
MLC
.
The transforming growth factor-ss superfamily cytokine macrophage inhibitory cytokine-1 is present in high concentrations in the serum of pregnant women
.
J Clin Endocrinol Metab
.
2000
;
85
(
12
):
4781
8
.
5.
Kleinert
M
,
Clemmensen
C
,
Sjøberg
KA
,
Carl
CS
,
Jeppesen
JF
,
Wojtaszewski
JFP
.
Exercise increases circulating GDF15 in humans
.
Mol Metab
.
2018
;
9
:
187
91
.
6.
Zhang
M
,
Sun
W
,
Qian
J
,
Tang
Y
.
Fasting exacerbates hepatic growth differentiation factor 15 to promote fatty acid β-oxidation and ketogenesis via activating XBP1 signaling in liver
.
Redox Biol
.
2018
;
16
:
87
96
.
7.
Hsu
L-A
,
Wu
S
,
Juang
J-MJ
,
Chiang
F-T
,
Teng
M-S
,
Lin
J-F
.
Growth differentiation factor 15 may predict mortality of peripheral and coronary artery diseases and correlate with their risk factors
.
Mediators Inflamm
.
2017
;
2017
:
9398401
.
8.
Teng
M-S
,
Hsu
L-A
,
Juan
S-H
,
Lin
W-C
,
Lee
M-C
,
Su
C-W
.
A GDF15 3′ UTR variant, rs1054564, results in allele-specific translational repression of GDF15 by hsa-miR-1233-3p
.
PLoS One
.
2017
;
12
(
8
):
e0183187
.
9.
Baek
SJ
,
Kim
KS
,
Nixon
JB
,
Wilson
LC
,
Eling
TE
.
Cyclooxygenase inhibitors regulate the expression of a TGF-beta superfamily member that has proapoptotic and antitumorigenic activities
.
Mol Pharmacol
.
2001
;
59
(
4
):
901
8
.
10.
Li
P-X
,
Wong
J
,
Ayed
A
,
Ngo
D
,
Brade
AM
,
Arrowsmith
C
.
Placental transforming growth factor-β is a downstream mediator of the growth arrest and apoptotic response of tumor cells to DNA damage and p53 overexpression
.
J Biol Chem
.
2000
;
275
(
26
):
20127
35
.
11.
Brown
DA
,
Lindmark
F
,
Stattin
P
,
Bälter
K
,
Adami
H-O
,
Zheng
SL
.
Macrophage inhibitory cytokine 1: a new prognostic marker in prostate cancer
.
Clin Cancer Res
.
2009
;
15
(
21
):
6658
64
.
12.
Kempf
T
,
Guba-Quint
A
,
Torgerson
J
,
Magnone
MC
,
Haefliger
C
,
Bobadilla
M
.
Growth differentiation factor 15 predicts future insulin resistance and impaired glucose control in obese nondiabetic individuals: results from the XENDOS trial
.
Eur J Endocrinol
.
2012
;
167
(
5
):
671
8
.
13.
Peiró
ÓM
,
García-Osuna
Á
,
Ordóñez-Llanos
J
,
Cediel
G
,
Bonet
G
,
Rojas
S
.
Long-term prognostic value of growth differentiation factor-15 in acute coronary syndromes
.
Clin Biochem
.
2019
;
73
:
62
9
.
14.
Maresca
A
,
Del Dotto
V
,
Romagnoli
M
,
La Morgia
C
,
Di Vito
L
,
Capristo
M
.
Expanding and validating the biomarkers for mitochondrial diseases
.
J Mol Med
.
2020
;
98
(
10
):
1467
78
.
15.
Lasaad
S
,
Walter
C
,
Rafael
C
,
Morla
L
,
Doucet
A
,
Picard
N
.
GDF15 mediates renal cell plasticity in response to potassium depletion in mice
.
Acta Physiol
.
2023
;
239
(
2
):
e14046
.
16.
Sangkhae
V
,
Nemeth
E
.
Regulation of the iron homeostatic hormone hepcidin
.
Adv Nutr
.
2017
;
8
(
1
):
126
36
.
17.
Wang
C
,
Fang
Z
,
Zhu
Z
,
Liu
J
,
Chen
H
.
Reciprocal regulation between hepcidin and erythropoiesis and its therapeutic application in erythroid disorders
.
Exp Hematol
.
2017
;
52
:
24
31
.
18.
Joachim
JH
,
Mehta
KJ
.
Hepcidin in hepatocellular carcinoma
.
Br J Cancer
.
2022
;
127
(
2
):
185
92
.
19.
Johnen
H
,
Lin
S
,
Kuffner
T
,
Brown
DA
,
Tsai
VW-W
,
Bauskin
AR
.
Tumor-induced anorexia and weight loss are mediated by the TGF-β superfamily cytokine MIC-1
.
Nat Med
.
2007
;
13
(
11
):
1333
40
.
20.
DíAZ
M
,
CampderróS
L
,
Guimaraes
MP
,
LóPEZ-Bermejo
A
,
de Zegher
F
,
Villarroya
F
.
Circulating growth-and-differentiation factor-15 in early life: relation to prenatal and postnatal growth and adiposity measurements
.
Pediatr Res
.
2019
;
87
(
5
):
897
902
.
21.
You
AS
,
Kalantar-Zadeh
K
,
Lerner
L
,
Nakata
T
,
Lopez
N
,
Lou
L
.
Association of growth differentiation factor 15 with mortality in a prospective hemodialysis cohort
.
Cardiorenal Med
.
2017
;
7
(
2
):
158
68
.
22.
Kleinert
M
,
Bojsen-Møller
KN
,
Jørgensen
NB
,
Svane
MS
,
Martinussen
C
,
Kiens
B
.
Effect of bariatric surgery on plasma GDF15 in humans
.
Am J Physiol Endocrinol Metab
.
2019
316
4
E615
21
.
23.
Dolo
PR
,
Yao
L
,
Liu
PP
,
Widjaja
J
,
Meng
S
,
Li
C
.
Effect of sleeve gastrectomy on plasma growth differentiation factor-15 (GDF15) in human
.
Am J Surg
.
2020
;
220
(
3
):
725
30
.
24.
Tsai
VW
,
Zhang
HP
,
Manandhar
R
,
Lee-Ng
KKM
,
Lebhar
H
,
Marquis
CP
.
Treatment with the TGF-b superfamily cytokine MIC-1/GDF15 reduces the adiposity and corrects the metabolic dysfunction of mice with diet-induced obesity
.
Int J Obes
.
2018
;
42
(
3
):
561
71
.
25.
Tran
T
,
Yang
J
,
Gardner
J
,
Xiong
Y
.
GDF15 deficiency promotes high fat diet-induced obesity in mice
.
PLoS One
.
2018
;
13
(
8
):
e0201584
.
26.
Tsai
VW-W
,
Macia
L
,
Johnen
H
,
Kuffner
T
,
Manadhar
R
,
Jørgensen
SB
.
TGF-B superfamily cytokine MIC-1/GDF15 is a physiological appetite and body weight regulator
.
PLoS One
.
2013
;
8
(
2
):
e55174
.
27.
Chung
HK
,
Ryu
D
,
Kim
KS
,
Chang
JY
,
Kim
YK
,
Yi
H-S
.
Growth differentiation factor 15 is a myomitokine governing systemic energy homeostasis
.
J Cell Biol
.
2017
;
216
(
1
):
149
65
.
28.
Tsai
VW-W
,
Zhang
HP
,
Manandhar
R
,
Schofield
P
,
Christ
D
,
Lee-Ng
KKM
.
GDF15 mediates adiposity resistance through actions on GFRAL neurons in the hindbrain AP/NTS
.
Int J Obes
.
2019
;
43
(
12
):
2370
80
.
29.
Wang
X
,
Chrysovergis
K
,
Kosak
J
,
Eling
TE
.
Lower NLRP3 inflammasome activity in NAG-1 transgenic mice is linked to a resistance to obesity and increased insulin sensitivity
.
Obesity
.
2014
;
22
(
5
):
1256
63
.
30.
Schernthaner-Reiter
MH
,
Itariu
BK
,
Krebs
M
,
Promintzer-Schifferl
M
,
Stulnig
TM
,
Tura
A
.
GDF15 reflects beta cell function in obese patients independently of the grade of impairment of glucose metabolism
.
Nutr Metab Cardiovasc Dis
.
2019
;
29
(
4
):
334
42
.
31.
Frimodt-Møller
M
,
von Scholten
BJ
,
Reinhard
H
,
Jacobsen
PK
,
Hansen
TW
,
Persson
FI
.
Growth differentiation factor-15 and fibroblast growth factor-23 are associated with mortality in type 2 diabetes: an observational follow-up study
.
PLoS One
.
2018
;
13
(
4
):
e0196634
.
32.
Johnen
H
,
Kuffner
T
,
Brown
DA
,
Wu
BJ
,
Stocker
R
,
Breit
SN
.
Increased expression of the TGF-b superfamily cytokine MIC-1/GDF15 protects ApoE(−/−) mice from the development of atherosclerosis
.
Cardiovasc Pathol
.
2012
;
21
(
6
):
499
505
.
33.
Asrih
M
,
Wei
S
,
Nguyen
TT
,
Yi
H-S
,
Ryu
D
,
Gariani
K
.
Overview of growth differentiation factor 15 in metabolic syndrome
.
J Cell Mol Med
.
2023
;
27
(
9
):
1157
67
.
34.
Wang
D
,
Day
EA
,
Townsend
LK
,
Djordjevic
D
,
Jørgensen
SB
,
Steinberg
GR
.
GDF15: emerging biology and therapeutic applications for obesity and cardiometabolic disease
.
Nat Rev Endocrinol
.
2021
;
17
(
10
):
592
607
.
35.
Breit
SN
,
Tsai
VW-W
,
Brown
DA
.
Targeting obesity and cachexia: identification of the GFRAL receptor–MIC-1/GDF15 pathway
.
Trends Mol Med
.
2017
;
23
(
12
):
1065
7
.
36.
Day
EA
,
Ford
RJ
,
Smith
BK
,
Mohammadi-Shemirani
P
,
Morrow
MR
,
Gutgesell
RM
.
Metformin-induced increases in GDF15 are important for suppressing appetite and promoting weight loss
.
Nat Metab
.
2019
;
1
(
12
):
1202
8
.
37.
Coll
AP
,
Chen
M
,
Taskar
P
,
Rimmington
D
,
Patel
S
,
Tadross
JA
.
GDF15 mediates the effects of metformin on body weight and energy balance
.
Nature
.
2020
;
578
(
7795
):
444
8
.
38.
Yang
L
,
Chang
C-C
,
Sun
Z
,
Madsen
D
,
Zhu
H
,
Padkjær
SB
.
GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand
.
Nat Med
.
2017
;
23
(
10
):
1158
66
.
39.
Hsu
J-Y
,
Crawley
S
,
Chen
M
,
Ayupova
DA
,
Lindhout
DA
,
Higbee
J
.
Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15
.
Nature
.
2017
;
550
(
7675
):
255
9
.
40.
Mullican
SE
,
Lin-Schmidt
X
,
Chin
C-N
,
Chavez
JA
,
Furman
JL
,
Armstrong
AA
.
GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates
.
Nat Med
.
2017
;
23
(
10
):
1150
7
.
41.
Emmerson
PJ
,
Wang
F
,
Du
Y
,
Liu
Q
,
Pickard
RT
,
Gonciarz
MD
.
The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL
.
Nat Med
.
2017
;
23
(
10
):
1215
9
.
42.
Sabatini
PV
,
Frikke-Schmidt
H
,
Arthurs
J
,
Gordian
D
,
Patel
A
,
Rupp
AC
.
GFRAL-expressing neurons suppress food intake via aversive pathways
.
Proc Natl Acad Sci U S A
.
2021
;
118
(
8
):
e2021357118
.
43.
Worth
AA
,
Shoop
R
,
Tye
K
,
Feetham
CH
,
D’Agostino
G
,
Dodd
GT
.
The cytokine GDF15 signals through a population of brainstem cholecystokinin neurons to mediate anorectic signalling
.
Elife
.
2020
;
9
:
e55164
.
44.
Kanta
JM
,
Deisen
L
,
Johann
K
,
Holm
S
,
Lundsgaard
A
,
Lund
J
.
Dietary medium-chain fatty acids reduce food intake via the GDF15-GFRAL axis in mice
.
Mol Metab
.
2023
;
74
:
101760
.
45.
Miyake
M
,
Zhang
J
,
Yasue
A
,
Hisanaga
S
,
Tsugawa
K
,
Sakaue
H
.
Integrated stress response regulates GDF15 secretion from adipocytes, preferentially suppresses appetite for a high-fat diet and improves obesity
.
iScience
.
2021
;
24
(
12
):
103448
.
46.
Patel
S
,
Alvarez-Guaita
A
,
Melvin
A
,
Rimmington
D
,
Dattilo
A
,
Miedzybrodzka
EL
.
GDF15 provides an endocrine signal of nutritional stress in mice and humans
.
Cell Metab
.
2019
;
29
(
3
):
707
18.e8
.
47.
Chrysovergis
K
,
Wang
X
,
Kosak
J
,
Lee
SH
,
Kim
JS
,
Foley
JF
.
NAG-1/GDF-15 prevents obesity by increasing thermogenesis, lipolysis and oxidative metabolism
.
Int J Obes
.
2014
;
38
(
12
):
1555
64
.
48.
Wang
D
,
Townsend
LK
,
Desormeaux
GJ
,
Frangos
SM
,
Batchuluun
B
,
Dumont
L
.
GDF15 promotes weight loss by enhancing energy expenditure in muscle
.
Nature
.
2023
;
619
(
7968
):
143
50
.
49.
Xiong
Y
,
Walker
K
,
Min
X
,
Hale
C
,
Tran
T
,
Komorowski
R
.
Long-acting MIC-1/GDF15 molecules to treat obesity: evidence from mice to monkeys
.
Sci Transl Med
.
2017
9
412
eaan8732
.
50.
Borner
T
,
Shaulson
ED
,
Ghidewon
MY
,
Barnett
AB
,
Horn
CC
,
Doyle
RP
.
GDF15 induces anorexia through nausea and emesis
.
Cell Metab
.
2020
;
31
(
2
):
351
62.e5
.
51.
Lertpatipanpong
P
,
Lee
J
,
Kim
I
,
Eling
T
,
Oh
SY
,
Seong
JK
.
The anti-diabetic effects of NAG-1/GDF15 on HFD/STZ-induced mice
.
Sci Rep
.
2021
;
11
(
1
):
15027
.
52.
Lu
JF
,
Zhu
MQ
,
Xie
BC
,
Shi
XC
,
Liu
H
,
Zhang
RX
.
Camptothecin effectively treats obesity in mice through GDF15 induction
.
PLoS Biol
.
2022
;
20
(
2
):
e3001517
.
53.
Guillaume
M
,
Riant
E
,
Fabre
A
,
Raymond-Letron
I
,
Buscato
M
,
Davezac
M
.
Selective liver estrogen receptor α modulation prevents steatosis, diabetes, and obesity through the anorectic growth differentiation factor 15 hepatokine in mice
.
Hepatol Commun
.
2019
;
3
(
7
):
908
24
.
54.
Zhang
H
,
Fealy
CE
,
Kirwan
JP
.
Exercise training promotes a GDF15-associated reduction in fat mass in older adults with obesity
.
Am J Physiol Endocrinol Metab
.
2019
316
5
E829
36
.
55.
Frikke-Schmidt
H
,
Hultman
K
,
Galaske
JW
,
Jørgensen
SB
,
Myers
MG
,
Seeley
RJ
.
GDF15 acts synergistically with liraglutide but is not necessary for the weight loss induced by bariatric surgery in mice
.
Mol Metab
.
2019
;
21
:
13
21
.
56.
Zhang
H
,
Mulya
A
,
Nieuwoudt
S
,
Vandanmagsar
B
,
Mcdowell
R
,
Heintz
EC
.
GDF15 mediates the effect of skeletal muscle contraction on glucose-stimulated insulin secretion
.
Diabetes
.
2023
;
72
(
8
):
1070
82
.
57.
Borner
T
,
Wald
HS
,
Ghidewon
MY
,
Zhang
B
,
Wu
Z
,
De Jonghe
BC
.
GDF15 induces an aversive visceral malaise state that drives anorexia and weight loss
.
Cell Rep
.
2020
;
31
(
3
):
107543
.
58.
Ghidewon
M
,
Wald
HS
,
Mcknight
AD
,
De Jonghe
BC
,
Breen
DM
,
Alhadeff
AL
.
Growth differentiation factor 15 (GDF15) and semaglutide inhibit food intake and body weight through largely distinct, additive mechanisms
.
Diabetes Obes Metab
.
2022
;
24
(
6
):
1010
20
.
59.
Choi
MJ
,
Jung
S-B
,
Lee
SE
,
Kang
SG
,
Lee
JH
,
Ryu
MJ
.
An adipocyte-specific defect in oxidative phosphorylation increases systemic energy expenditure and protects against diet-induced obesity in mouse models
.
Diabetologia
.
2020
;
63
(
4
):
837
52
.
60.
Ost
M
,
Igual Gil
C
,
Coleman
V
,
Keipert
S
,
Efstathiou
S
,
Vidic
V
.
Muscle-derived GDF15 drives diurnal anorexia and systemic metabolic remodeling during mitochondrial stress
.
EMBO Rep
.
2020
;
21
(
3
):
e48804
.
61.
Moon
JS
,
Goeminne
LJE
,
Kim
JT
,
Tian
JW
,
Kim
S-H
,
Nga
HT
.
Growth differentiation factor 15 protects against the aging-mediated systemic inflammatory response in humans and mice
.
Aging Cell
.
2020
;
19
(
8
):
e13195
.
62.
Jung
SB
,
Choi
MJ
,
Ryu
D
,
Yi
HS
,
Lee
SE
,
Chang
JY
.
Reduced oxidative capacity in macrophages results in systemic insulin resistance
.
Nat Commun
.
2018
;
9
(
1
):
1551
.
63.
Nakayasu
ES
,
Syed
F
,
Tersey
SA
,
Gritsenko
MA
,
Mitchell
HD
,
Chan
CY
.
Comprehensive proteomics analysis of stressed human islets identifies GDF15 as a target for type 1 diabetes intervention
.
Cell Metab
.
2020
;
31
(
2
):
363
74.e6
.
64.
Laurens
C
,
Parmar
A
,
Murphy
E
,
Carper
D
,
Lair
B
,
Maes
P
.
Growth and differentiation factor 15 is secreted by skeletal muscle during exercise and promotes lipolysis in humans
.
JCI insight
.
2020
;
5
(
6
):
e131870
.
65.
Suriben
R
,
Chen
M
,
Higbee
J
,
Oeffinger
J
,
Ventura
R
,
Li
B
.
Antibody-mediated inhibition of GDF15-GFRAL activity reverses cancer cachexia in mice
.
Nat Med
.
2020
;
26
(
8
):
1264
70
.
66.
Flicker
D
,
Sancak
Y
,
Mick
E
,
Goldberger
O
,
Mootha
V
.
Exploring the in vivo role of the mitochondrial calcium uniporter in Brown fat bioenergetics
.
Cell Rep
.
2019
;
27
(
5
):
1364
75.e5
.
67.
Forsström
S
,
Jackson
C
,
Carroll
C
,
Kuronen
M
,
Pirinen
E
,
Pradhan
S
.
Fibroblast growth factor 21 drives dynamics of local and systemic stress responses in mitochondrial myopathy with mtDNA deletions
.
Cell Metab
.
2019
;
30
(
6
):
1040
54.e7
.
68.
Costa-Mattioli
M
,
Walter
P
.
The integrated stress response: from mechanism to disease
.
Science
.
2020
368
6489
eaat5314
.
69.
Gil
CI
,
Ost
M
,
Kasch
J
,
Schumann
S
,
Heider
S
,
Klaus
S
.
Role of GDF15 in active lifestyle induced metabolic adaptations and acute exercise response in mice
.
Sci Rep
.
2019
;
9
(
1
):
20120
.
70.
Li
D
,
Zhang
H
,
Zhong
Y
.
Hepatic GDF15 is regulated by CHOP of the unfolded protein response and alleviates NAFLD progression in obese mice
.
Biochem Biophys Res Commun
.
2018
;
498
(
3
):
388
94
.
71.
L’Homme
L
,
Sermikli
B
,
Staels
B
,
Piette
J
,
Legrand-Poels
S
,
Dombrowicz
D
.
Saturated fatty acids promote GDF15 expression in human macrophages through the PERK/eIF2/CHOP signaling pathway
.
Nutrients
.
2020
;
12
(
12
):
3771
.
72.
Apolzan
JW
,
Venditti
EM
,
Edelstein
SL
,
Knowler
WC
,
Dabelea
D
,
Boyko
EJ
.
Long-term weight loss with metformin or lifestyle intervention in the diabetes prevention program outcomes study
.
Ann Intern Med
.
2019
;
170
(
10
):
682
90
.
73.
Johnson
AA
,
Shokhirev
MN
,
Wyss-Coray
T
,
Lehallier
B
.
Systematic review and analysis of human proteomics aging studies unveils a novel proteomic aging clock and identifies key processes that change with age
.
Ageing Res Rev
.
2020
;
60
:
101070
.