Obesity is a major public health problem, affecting millions of individuals worldwide. According to World Obesity Atlas (1), the proportion of the obese population (BMI ≥ 30) will reach 17% in 2025, and 20% in 2030 affecting more than 1.5 billion people. It is noteworthy to mention that COVID-19 pandemic has worsened the obesity epidemic, and the restrictions from 2020 to 2022 have increased the risk of weight gain by increasing sedentary and unhealthy dietary behaviors, and significantly reduced access to health care (2).

Obesity is a complex multifactorial disease, meaning it is caused by multiple interacting factors, including genetics, environmental, and behavioral factors (3). The long-term serious effect of obesity lies in the increasing likelihood of many diseases, including insulin resistance (IR) and type 2 diabetes (T2D) (4), chronic kidney disease (CKD) (5), non-alcoholic fatty liver disease (NAFLD), and some cancers (6). Additionally, both obesity and T2D increase the prevalence of cardiovascular disorders (CVDs) (7). Although obesity and BMI represent a good indicator of the overall metabolic health profile, studies have shown that the distribution of body fat into fat depots plays a more important role in the co-morbidity of the metabolic diseases (8). This indicates that BFD measurements along BMI need to be considered to assess metabolic health. These measurements include simple waist to hip ratio, where the waist circumference (reflecting abdominal adiposity) is divided by the hip circumference [reflecting gluteal femoral (GF) fat adiposity]. Other more accurate measurements include body imaging to measure actual fat depot sizes.

Adipose tissue functions not only as a fat storage organ, but also as a dynamic organ (9); therefore, fat storage in different depots have diverse impact on human health. In fact, each fat depot contributes differently as metabolic and endocrine organ, leading to different levels of metabolic disorders (10). It is well established that over-accumulating fat in the abdominal fat depot is associated with metabolic disorders; Increases of abdominal adiposity as opposed to overall adiposity, is associated with increases in the likelihood of getting T2D and CVDs 4 (11). Some studies showed hip circumference and thigh fat adiposity alone as an independent indicator of obesity-related metabolic risks (12). More recent evidence suggests that GF fat depot shows a protective role against these metabolic disorders; fat storage in the GF depot is preferred over storage in the abdominal depot to gain a metabolically healthy state (13–16). These opposing relationships reflect the unique intrinsic characteristics of different fat depots.

Explaining the factors that lead to distinct BFD and resolving the mechanisms behind the protective role of some depots, may help in finding novel therapeutic venues for preventing or treating obesity-related diseases. In this review, we summarized the important factors affecting BFD, whether uncontrollable (genetics, epigenetic factors, age, and hormonal profile) or controllable (diet, exercise, and consumption of certain medications). Then, we compiled detailed evidence supporting the protective role of the GF fat depot against metabolic disorders, including IR, T2D, and CVDs. Finally, we summarized the reported possible mechanisms explaining how this protection is accomplished.

Adipose fat depots are the specific location where the fat tissue is built and located in the body. The human body stores fat in 2 anatomically and physiologically distinct fat depots; subcutaneous adipose tissue (SCAT) and visceral adipose tissue (VAT). SCAT is located between the skin and superficial musculature, and it can be further classified into superficial SCAT and deep SCAT (17). The main depots where SCAT is stored are the inguinal region (GF regions), and the anterior and the back of the abdominal wall as shown in Figure 1. On the other hand, VAT depot, also known as intra-abdominal fat, is the fat tissue stored within/between the visceral organs, such as liver and intestines (8). Physiologically, VAT is more vascular, innervated, and contains less preadipocyte differentiating capacity, greater percentage of large adipocytes and larger number of inflammatory and immune cells as compared to SCAT (18). Individuals with enhanced abdominal obesity, more specifically with high VAT depot content are referred to apple shaped, as compared to pear shaped individuals that express higher GF content (19), as illustrated in Graphical Abstract.

The GF fat as a combined depot is referred to as gluteal-femoral fat (GF fat/GF adipose tissue) as shown in Figure 1. In literature, GF fat is referred to as thigh, hip, or lower body fat, and could be further classified into different depots. These depots differ in their biology, histology, and physiological role. GF subcutaneous adipose tissue (GF-SCAT) is the fat tissue stored under the skin of the lower body part. Another thigh fat depot is the thigh intermuscular adipose tissue (thigh IMAT) illustrated in Figure 1, which is considered as an ectopic fat depot; fat stored in tissues other than specialized adipose tissue, skeletal muscle tissue in this case (8). In the following section, we discussed the factors affecting BFD, favoring specific depots over the others.

Body fat distribution (BFD) is affected and mediated by multiple factors. Genetic background plays a significant role in determining BFD. Studies have shown that certain genes are associated with increased abdominal fat, while others are associated with increased fat in the hips and thighs (20–25). Epigenetic differences, which impact obesity, may also have an influence on body fat distribution (26–28). Ethnicity, aging, and hormonal changes also play a role in BFD (7, 29, 30). On the other hand, certain factors can be induced to manipulate BFD. Diet restriction and exercise can lead to fat reduction in the abdominal region (31). Certain medications, such as those used to treat diabetes or high blood pressure, can also lead to a redistribution in body fat (19). The factors that affect BFD are summarized in Table 1.

Insulin resistance (IR) is a defined as a state where the body cells become irresponsive to the physiological insulin levels secreted in the blood (46). IR is a risk factor for many chronic metabolic disorders. The major consequence of IR is the progression of type 2 diabetes, where individuals diagnosed with IR are expected to develop T2D in 5 ~ 10 years (46). T2D is highly diverse disease. To personalize the treatment of T2D, a study attempted to classify the disease into clusters, depending on six variables: including glutamate decarboxylase antibodies, age, BMI, HbA1c, and homoeostatic model assessment 2 estimates of β-cell function and insulin resistance. The significance of this classification is to generate a way to estimate the risk of diabetic complications, which they successfully showed in their study. According to the researchers, one cluster (highest insulin resistance) showed more association to kidney disease, another cluster (insulin deficient) showed the highest risk of retinopathy, while a third cluster associated with higher fat liver, indicating a relevance of VAT to IR (47).

Previously, obesity was believed to be a major leading cause of IR. However, recent investigation showed that abdominal obesity is positively associated with IR, while considerable debate remains concerning the potential of a positive effect of thigh fat in metabolic protection against IR progression (19). This theory explains the metabolically healthy obese individuals and how their bodies escape the negative metabolic consequences of obesity (48). Thigh fat is protective against IR; a study demonstrated that lower thigh SCAT and higher VAT both contribute to insulin resistance profile. The study was conducted on a cohort from the general population, it demonstrated that high thigh SCAT alone or low VAT alone were positively associated with IS state while Individuals with combination of high SCAT and low IMAT had the highest IS state among all groups (49). A more recent study investigated both thigh fat depots (thigh SCAT and thigh IMAT) in a female cohort. They showed that higher thigh-SCAT and lower thigh-IMAT are associated with insulin sensitivity (14). The same findings were supported with studies done on children obese cohort (age of 7–17 years old), where a study suggested a protective effect of thigh fat, and its association to a healthy metabolic profile [more favorable HOMA-IR score, triglyceride serum level, systolic blood pressure (SBP), C-reactive protein (CRP), resistin, high-density lipoprotein (HDL), cholesterol, adiponectin, and blood lipid profile] (15). Whereas another study conducted on postmenopausal women suggested that thigh fat was associated with a favorable metabolic profile, including serum triglycerides, HDL-cholesterol, and various IR markers (50). Due to the reported association between thigh fat and protection against IR, a study suggested that regional adiposity, including thigh fat size could be used as a predictive way to predict the risk of developing IR. They reported that each increase in thigh fat led to a 59% decrease in the odds of becoming insulin resistant, independently from confounders (age, BMI, visceral adiposity, and gender) (51).

It has been reported that a larger gluteal femoral fat is associates with lower prevalence of IR, prediabetes, and dyslipidemia (52). However, as explained in the previous section, not all thigh fat seems to be protective. A study assessed critical biomarkers and how their levels are different among individuals with different BFDs. The findings suggested a significantly lower insulin resistance and triglycerides levels in individuals with higher GF fat (13), but according to Snijder et al. (52), only thigh-SCAT was found to be associated with favorable metabolic profiles. Higher thigh-SCAT was shown to be associated with lower transformed triglycerides (in both genders), higher HDL-cholesterol, and lower blood glucose level (in males only).

The revised studies showed how GF-SCAT is beneficial as a protective fat depot against metabolic disease. In contrast, IMAT is an ectopic depot for fat storage. In contrary with SCAT, fat deposition in IMAT is highly associated with increase IR and T2D (53). One suggested mechanism of how IMAT promotes IR progression is because fat accumulation within the thigh muscular tissue leads to reduced blood circulation, and decreased insulin uptake efficiency by the muscle cells (54). These studies confirm the association between GF SCAT levels, not GF IMAT, and developing IR leading to multiple metabolic disorders, including type 2 diabetes and cardiovascular disease as explained in the following section.

Cardiovascular diseases (CVDs) are a general term that describes a range of pathologies affecting the health of the heart, the blood vessels, or the pericardium. It is critical to study the risk factors affecting and leading to CVDs as these diseases can be fatal. Previous studies have shown a clear association between BFD and the risk of developing CVDs (19, 50, 55). While increased fat storage in the abdominal depot; mainly ectopic visceral fat is associated with high CVDs progression risk, high GF fat storage was shown to be cardioprotective (56).

The cardioprotective role of GF fat has been confirmed in many studies involving diverse human subjects with different ages, BMIs, and diseases. As early as 1991, thigh fat has a negative association with cardiovascular diseases was first hypothesized. High thigh fat was shown to contribute to lipoprotein plasma profile; an indicator of lower risk of cardiovascular diseases (57). Following that finding, more research groups started showing the same correlation among different models. Accumulating evidence shows an association between increased lower body adiposity and GF fat and healthy lipid profile. Many studies showed evidence that elevated GF fat is associated with better serum lipid levels, including lower low-density lipoprotein-cholesterol profile, and higher high-density-cholesterol levels, which are indicators of improved cardiovascular health⁸. Van Pelt et al. (50) showed an enhanced triglycerides level in individuals with higher GT fat as compared to others with the same BMI.

In addition to improved serum lipid profile, increased GF mass has been shown to be directly associated with enhanced vascular health, including lower aortic calcification, decreased progression of present aortic calcification, as well as decreased arterial stiffness in a women cohort (58). Furthermore, studies showed a direct effect between GF fat and cardiac diseases. Yusuf et al. (59), conducted a study that involved 27,000 participants, they showed a negative association between hip circumference and the risk of myocardial infarction. Another study confirmed that a larger hip circumference is associated with lower risk of developing coronary heart disease in a population involving both genders (60). Shay et al. (16) reported that women characterized with higher GF fat content and suffer from type-1-diabetes have shown less risk of developing coronary artery disease, which was not shown in men.

The protective effect of GF fat against CVD risk persists even with aging. A study was conducted on healthy elderly women, they confirmed a strong association between GF-fat and protection against vascular damage (55). These studies confirm the tight association between GF levels and the risk of CVDs. More studies were well revised by Manolopoulos et al. (61). In the following section, we will revise the reported mechanisms that explain this association, as well as the possible mechanisms that need more investigation to be proven.

As mentioned previously, thigh fat shows protective properties against IR and CVDs. While the mechanism behind this association remains not fully understood, research suggests three major mechanisms by which this protection is achieved. These mechanisms ultimately enhance metabolic health and lower the risk of developing IR and CVDs.

The BFD is a highly accurate indicator of metabolic health due to its association with IR, T2D, and CVDs. Th factors that contribute to fat distribution include genetic background, age, hormonal changes, lifestyle (diet and exercise), and medication consumption. It is necessary to understand BFD, as fat storage in certain depots shows a protective effect against metabolic disorders. The gluteal femoral fat depot is one of these depots. Many reports showed its protection against IR, and its metabolic complications (T2D and CVDs). The mechanisms of this protection include three major mechanisms: first, GF depot demonstrates a lower rate of lipolysis. Second, GF depot acts as a metabolic reservoir of excess lipids, preventing them from being stored in the visceral fat depot. And finally, GF depot has a unique physiological nature of GF in terms of lipoproteins, adipokines, and cytokines secretion, it produces protective cytokines (leptin and adiponectin) in higher levels as compared to other depots, while secreting lower levels of proinflammatory adipokines and cytokines (DPP4 ND IL-6). The protective effect of GF fat is interesting, and the mechanisms behind it is still an active area of research that merits further studying to be fully understood.

MA: Investigation, Visualization, Writing – original draft. KN: Supervision, Writing – review & editing. ME: Conceptualization, Funding acquisition, Project administration, Supervision, Writing – review & editing.