Obesity and diabetes are global health problems with a significant burden on the world economy and are responsible for numerous health-related problems worldwide1. The primary cause of obesity is multifactorial and results from a complex interplay of genetic, environmental, and behavioural factors. The interaction among these factors contributes to the complexity of obesity and poses challenges for its treatment, given the intricate relationships among various genes and other risk factors such as environmental and lifestyle factors2. While an individual’s genetic background is one of the essential factors contributing to obesity, it's important to note that the basis of obesity is not solely genetic3. Evidence suggests that genes often need to be closely linked with environmental and lifestyle risk factors to impact weight 4. Therefore, gaining a deeper understanding of the common causes of obesity and weight gain is crucial. Lifestyle interventions such as physical activity and diet represent the initial therapeutic approach for managing obesity and diabetes. However, there is an urgent need for novel therapies.
Growth differentiation factor 15 (GDF-15) is a member of the transforming growth factor-β (TGF-B) superfamily and is highly expressed in several tissues, including the liver, heart, intestine, and kidneys5–7. It was primarily identified as a soluble factor produced by macrophages and cancer cells. GDF-15 is induced in all cell types in response to mitochondrial and endoplasmic reticulum stress, which is commonly observed in various conditions such as cancer, diabetes, inflammation, and chronic liver and kidney disease8. Increased body weight and adipose tissue mass are also positively associated with elevated GDF-15 expression and release 9. Over the past decade, many investigations have emphasized the importance of GDF-15 in several diseases. These investigations demonstrated the significant clinical relevance of GDF-15 as a diagnostic and prognostic biomarker for conditions including prostate cancer, pulmonary disease, diabetic cardiomyopathy, heart failure, and mitochondrial disease10. Notably, a study utilizing human liver single-cell RNA sequencing has shown increased expression of GDF-15 across all hepatocytes, which supports the strong correlation between GDF-15 levels and non-alcoholic fatty liver disease (NAFLD), and obesity11. Several regulatory pathways have been proposed to explain the increased expression and secretion of GDF-15. For instance, the stress-responsive transcription factor p53 and early growth response factor-1 (EGR1) have been described as key regulators of GDF-1512. Moreover, activation of AMP-activated protein kinase (AMPK) increases GDF-15 expression, and its transcription requires the activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP). Both ATF4 and CHOP are activated by mitochondrial stress and are commonly associated with obesity and insulin resistance13.
In animal studies, GDF-15 promotes weight loss by reducing fat mass and adiposity, improving insulin sensitivity and glucose tolerance while maintaining energy expenditure8. However, there has also been a claim that GDF-15 does not change energy expenditure but suppresses food intake through its direct effect on the area postrema and nucleus tractus, which are highly enriched in the glial cell-derived neurotrophic factor (GDNF) family receptor α-like (GFRAL), known for its high affinity to GDF-1514. Although the exact region of the brain that contributes to the reduction in food intake is not fully understood, several mechanistic pathways, including food preferences, nausea, vomiting, delayed gastric emptying, and taste aversion were proposed15. These proposed mechanistic pathways appear to be independent of the effects of leptin and glucagon-like peptide 1 (GLP-1)15,16.
Obesity is a risk factor for type 2 diabetes mellitus (T2DM), and some evidence from animal studies suggests that treatment with GDF-15 decreases body weight and glucose levels, primarily due to the loss of fat mass and reduced food intake16. However, a recent study proposed that GDF-15 decreases glucose levels independently of changes in body weight but through stimulating insulin secretion17. On the other hand, chronic low-grade inflammation is a culprit for insulin resistance and other metabolic derangements. Several studies have shown that GDF-15 may improve glucose homeostasis by enhancing insulin secretion and reducing low-grade chronic inflammation18. Considerable data indicate that metformin, a commonly prescribed medication for diabetes management, is associated with increased GDF-15 stimulation, subsequently improving glycemic control and inducing weight loss19. A similar effect has been observed with high- and moderate-intensity exercise20,21. Non-alcoholic fatty liver disease (NAFLD), which reflects the degree of obesity and the risk for T2DM, is associated with increased expression and release of GDF-15, making it a potential biomarker for NAFLD and disease progression, particularly for worsening fibrosis and steatosis22.
Recognizing the pivotal role of Growth Differentiation Factor-15 (GDF-15) in metabolic disorders, it becomes imperative to explore its relationship with variables such as gender and ethnicity, particularly in regions where obesity and diabetes are prevalent. This study is designed to investigate the levels of GDF-15 in individuals afflicted with diabetes, obesity, and insulin resistance. Additionally, it seeks to identify specific metabolic characteristics linked to variations in GDF-15 levels. By focusing on these aspects, the research addresses a critical and specialized area of interest, shedding light on the intricate interplay between GDF-15 and prevalent metabolic conditions.