Obesity is defined by the presence of a body mass index (BMI) ≥ 30 kg/m², with normal range varying from 18.5 to 24.9 kg/m². A BMI between 25.0 to 29.9 kg/m² is considered overweight [22]. Obesity and being overweight are almost invariably caused by excessive caloric intake compared to the necessary amount, which in turns determines fat storage increase and adipocyte hypertrophy [23]. An unhealthy lifestyle is often the leading cause of obesity, but also genetic and epigenetic factors seem to play a very important role [24]. About 30% of the adult population in the world is overweight or obese, with western countries showing the highest prevalence. The Organization for Economic Cooperation and Development (OECD) estimated a prevalence for obesity ranging from 3.7% in Japan up to 38.2% in the US [25]. In the last two decades, the number of obese patients has tripled in Europe, where obesity is estimated to account for 7% of total healthcare costs [26]. However, the prevalence of obesity is nowadays constantly rising, even in developing countries [27,28], and rising childhood obesity rates portend worsening statistics [29].

According to the UK National Audit Office, obesity-related disorders cause significant loss in terms of both working days and deaths, with subsequent direct and indirect costs being estimated at approximately £480,000,000 and £2,150,000,000 per year, respectively [30]. In the U.S, the economic burden for obesity and its comorbidities was estimated to be around $147 billion in 2008 and $126 billion in 2016 [31,32].

Beyond these numbers, a large number of people is currently at risk of becoming obese, including children with familial history of obesity and/or metabolic syndrome, former smokers, lower social classes and older people [33,34,35,36]. As just mentioned, obesity is usually framed in the broader context of metabolic syndrome (or syndrome X), where it is associated with hypertriglyceridemia, atherosclerosis, reduced HDL, hypertension and impaired glucose tolerance [37]. In particular, metabolic syndrome is defined by the presence of three or more of the following criteria: (1) abdominal obesity (waist circumference ≥ 102 cm for men and ≥ 88 cm for women); (2) triglycerides ≥ 150 mg/dL; (3) high-density lipoprotein (HDL) cholesterol < 40 mg/dL for men and < 50 mg/dL for women; (4) systolic blood pressure ≥ 130 mmHg and/or diastolic blood pressure ≥ 85 mmHg and (5) fasting serum glucose ≥ 100 mg/dL [38].

One of the main issues in obese subjects is T2D, which is notably associated with insulin resistance [39,40,41]. Obese subjects also have an increased cardiovascular risk which, like other obesity-related comorbidities, can be explained by lipid accumulation in internal organs. Atherosclerosis, due to lipid accumulation in arterial walls, has got a pivotal role in coronary and cerebrovascular disease [42]. However, obesity also leads to increased platelet activation, which is responsible for thrombosis and subsequent further inflammation, increasing the likelihood of developing ischemic complications [40]. Triglyceride accumulation in the liver causes non-alcoholic fatty liver disease [43]. Moreover, obesity is a well-established risk factor for cholelithiasis due to cholesterol gallstones [44].

Obesity is also associated with a large variety of other possible comorbid conditions, including endocrine, oncological neurological, dermatological, respiratory and psychological disorders. Alterations in the hypothalamic–pituitary–gonadal (HPG) axis are often present in obese subjects [44]. In particular, polycystic ovary syndrome (PCOS) is strictly connected with metabolic syndrome, and weight loss is often part of the therapeutic regimen [45]. Obesity also carries a higher risk of developing several types of malignancies, such as colorectal, gastric, liver and gallbladder, endometrial and esophageal cancer [46].

As for the neurological complications, obese patients are more likely to develop small fiber sensory neuropathy (SFSN) [47] and recent studies suggest a higher risk of developing a form of cortical atrophy similar to Alzheimer’s disease (AD) [48].

Ulcers, lymphedema, intertrigo, hidradenitis suppurativa, striae distensae, skin tags, acanthosis nigricans, psoriasis, acne, hirsutism and androgenetic alopecia are the main skin condition connected to obesity and metabolic syndrome [49].

Biomechanical stress caused by a high body mass is responsible for numerous comorbidities of the musculoskeletal, respiratory, gastrointestinal and skin systems [44].

From a respiratory point of view, obesity finally increases the risk of obstructive sleep apnea syndrome (OSAS), chronic obstructive pulmonary disease (COPD) and asthma [50]. Even if not universally accepted, obesity is also associated with psychiatric/psychological conditions, including anxiety and depression [51].

Most of the aforementioned comorbidities are associated with the low-grade inflammation which nearly invariably comes with obesity. In fact, adipocytes can produce proinflammatory cytokines, such as IL-6, therefore maintaining the pro-inflammatory state typical of obese subjects, as also confirmed by elevated levels of c-reactive protein (CRP) in these patients [52,53]. This chronic inflammatory state is associated with hemodynamic and cardiac changes due to excessive body weight and contributes to the increased likelihood of having heart failure for obese subjects [54].

A wound is defined as a disruption in the normal continuity of the skin. When the skin is injured, a series of events takes place in order to close and heal the area where the barrier is compromised [55]. Wound healing is an evolutionary-conserved process comprised of four sequential yet overlapping phases: hemostasis, inflammation, proliferation and remodeling (see Figure 2) [56]. These phases are strictly regulated through specific molecules that are expressed at different levels at each time interval [57].

The first process that takes place in the unwinding of wound healing consists of coagulation and hemostasis, aimed at stopping the bleeding while creating a temporary matrix for cells to infiltrate the site of injury [58]. In fact, not only does vascular smooth muscle contraction reduce the diameter of injured vessels as a mechanism of reflex, but also activation of the coagulation cascade allows platelets to form a clot with fibronectin, fibrin, vitronectin and thrombospondin [59]. Platelets also release several growth factors and cytokines when degranulating [60]. Growth factors and cytokines such as PDGF (platelet-derived growth factor), TGFβ (transforming growth factor β) and EGF (epidermal growth factor) activate neutrophils, macrophages, endothelial cells, fibroblasts and keratinocytes [61]. Then comes the inflammatory phase, where neutrophils, monocytes and macrophages flood to the site of injury [62]. Neutrophils help in removing cell debris and microorganisms that may have slipped into the wound via phagocytosis [63]. Macrophages also enter the site not only as professional phagocytes but also as regulatory cells secreting TGFα and TGFβ, HB-EGF (heparin-binding epidermal growth factor), FGFs (fibroblast growth factor) and collagenases [64,65]. Partially overlapping with the inflammatory phase, the proliferation stage is characterized by the activation, expansion and migration of fibroblasts, keratinocytes and endothelial cells [66]. Proliferation also involves the production of collagen, proteoglycans, hyaluronic acid and other ECM structural proteins that, along with fibroblast recruitment, give rise to granulation tissue [67]. Moreover, endothelial cells aid in forming new vessels and thus epithelization takes place [68]. Cytokines and growth factors activate keratinocytes so that they can migrate from the edges of the wound over the dermal matrix in order to close up the wound [69]. The expression of specific keratins, such as K6 and K16, is observed in migrating keratinocytes [70]. Lastly, collagenases, matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are secreted by fibroblasts in the remodeling phase [65].

Wound healing seems to be impaired in obese patients compared to subjects with a normal BMI (body mass index), despite the mechanism underlying such a difference not being totally understood [94]. A multidisciplinary team is thus often essential for optimal wound care management in obese patients [89]. Decreased vascularization can partially explain wound healing delay [95]. In fact, the increase in the size of the adipocytes typical of obesity is generally not accompanied by an adequate rise in the number of vessels [96]. This eventually leads to a fibrotic environment [97], characterized by reduced elastin and increased collagen V and VI levels [98].

Wound healing disorders seem to have a huge impact in obese patients, both form a clinical and a social point of view. Venous insufficiency, caused or worsened by an elevated intra-abdominal pressure due to fat accumulation in the abdominal area [99], can cause leakage of proteinaceous-like material in the interstitial space, which can eventually occlude smaller vessels [100]. The resulting reduction in oxygen tension not only affects the proliferative and remodeling phases but also increases the risk of wound infection through the impairment of leukocyte phagocytic properties [12,101]. Arterial ulcers are associated to PAD, with atherosclerosis [89] being a well-known comorbidity in obese patients affected by metabolic syndrome [102] and/or T2D. Pressure ulcers are demonstrated to be common among obese patients staying in nursing homes [103]. However, contrasting data regarding the effects of obesity on the risk of development of pressure ulcers have been published so far in other patient subpopulations [104,105].

Peripheral neuropathy is another factor that can cause, aggravate or delay wound healing, and often represent the leading cause of cutaneous ulcers in diabetic patients [106,107]. Microangiopathy often represents the principal cause of impaired wound healing in T2D patients, leading to reduced nerve vascularization, endothelial dysfunction and impaired microcirculation [108]. On the other hand, macroangiopathy causes the production of prothrombotic factors and prevents the formation of an efficient network of collateral vessels, thus contributing to the pathogenesis of chronic wounds [109]. Finally, Advanced Glycation End-products (AGEs) appear to play a role in delaying wound healing in diabetic patients, affecting both angiogenesis and [110] extracellular matrix (ECM) production and remodeling [111]. Recent studies have demonstrated insulin to promote cell migration, and insulin-based therapies have therefore been suggested to surmount the impact of insulin resistance on wound repairing [111,112]. In addition, leptin, an anti-obesity hormone, improves wound repairing by accelerating angiogenesis and promoting the proliferation, differentiation and migration of keratinocytes [113]. Leptin is physiologically produced by adipocytes and leads to a reduction in the caloric intake, regulating body weight. Nevertheless, a high-fat diet leads to a leptin-resistant condition over time, thus limiting the effects of this hormone [114]. In obese patients, high leptin plasma levels are associated with peripheral receptor resistance [115].