A summary of the most important mechanisms involved in nutrient metabolism and immune interactions, particularly in people with obesity and malnutrition, is provided in Table 1.

Table 1 Important Mechanisms.Adipose tissue and metabolism

Adipose tissue is categorized as white adipose tissue (WAT), which stores energy, and brown adipose tissue (BAT), which provides nonshivering thermogenesis [15]. WAT, which contains adipocytes with droplets of unilocular lipids, stores energy for later use and balances energy levels in the body [16]. In contrast, BAT potentially gets its color from mitochondrial membranes [17]. While WAT primarily serves as an energy reservoir, BAT functions more actively in heat production, especially during cold exposure [18]. The ability of BAT to generate heat stems from its high mitochondrial density, allowing fatty acid oxidation and heat production instead of energy storage. The thermogenic role of BAT is particularly critical for newborns, who rely on BAT to maintain body temperature in cold environments [19]. While animals, especially mice, have considerable quantities of BAT, it is common in only newborn humans and some adults [20].

Recent studies have revealed that BAT can also play a role in combating obesity and metabolic disorders [21, 22]. BAT activation was demonstrated to improve glucose metabolism and insulin sensitivity in adults, suggesting that increasing BAT activity could be a therapeutic approach to prevent obesity-related disorders. Furthermore, the discovery of “beige” adipocytes—initially white cells that may adopt brown-like features under specific stimuli—has offered new paths for developing obesity treatments that activate beige fat cells to promote thermogenesis and energy expenditure [23]. WAT can be found in different organs of the body, but its distribution is determined by hormones [24]. Therefore, unique organs containing WAT are found in the abdominal cavity: VAT and subcutaneous fat [24]. WAT can also be found in the kidney [25]. Since it can store and balance energy in the body, WAT helps regulate metabolism by excreting cytokines and hormones, including adiponectin and leptin, which regulate metabolism and feeding [26]. Excreted adipokines can modulate the immune system. The accumulation of visceral fat is related to metabolic disorders such as type II diabetes, dyslipidemia, and insulin resistance [27].

Adipose organs have been widely investigated in mice, and the data demonstrate that fat tissues develop from several progenitors. Numerous brown fat reservoirs are generated from Myf5+Pax3+ progenitors; however, some BAT depots can develop without expression of these transcription factors [28]. On the other hand, numerous white adipose cells are obtained from Myf5-Pax3- progenitors, with specific exceptions. For example, anterior subcutaneous WAT development critically relies on Myf5+Pax3+ progenitors [29]. There are distinctions in WAT between female and male rodents: for example, perigonadal WAT is obtained from Pax3- progenitors in females, whereas the development of this tissue depends on Pax3 in males [30]. For all these reasons, it is important to consider fat development when investigating people with obesity.

An acceptable body weight has been clearly defined clinically. A body mass index (BMI) of 18.5 to 25 kg/m2 is viewed as normal, whereas individuals with a BMI below 18 kg/m2 are underweight, those with a BMI above 25 kg/m2 are overweight, and those with a BMI greater than 30 kg/m2 are people with obesity [31]. Biologically, the differences among people with obesity, lean, and malnourished individuals are inadequately defined. With excessive consumption, the effect on overall body weight is insignificant because of the ability of adipose cells to increase energy density [32]. Nonetheless, excessive nutrient consumption has a significant effect on adipocytes. In addition, adipocytes can transition from a proadipogenic state to an antiadipogenic state at the endocrine level. Adiponectin is generated by adipose tissue and acts as an insulin homolog by impairing gluconeogenesis in the liver and increasing glucose uptake and free fatty acid esterification [33]. Mice deficient in adiponectin become insulin resistant and accumulate lipids in skeletal muscle [34]. The levels of adiponectin are negatively associated with the volume adipose tissue [35]. Under lean conditions, adipocytes generate considerable amounts of adiponectin, promoting fat accumulation in adipose tissue [36]. In people with obesity, adipocytes decrease adiponectin production in response to the adipokine leptin. In turn, leptin sends satiety signals to the central nervous system that stimulate the effects of ghrelin, the hunger-triggering cytokine generated by the gut [37]. Leptin also hinders lipogenesis while increasing glucose metabolism and preventing glucose accumulation in adipocytes [38]. The exogenous administration of leptin prevents the progression of obesity resulting from overfeeding due to low leptin levels [39].

Effects of adipokines on immune cells

Adipose tissue plays an important role in controlling metabolic processes and regulating immune cells. However, these processes rely on large amounts of adipokines. Fat has been considered an endocrine organ since the discovery of leptin, which led to the discovery of approximately fifty molecules produced by adipose tissue [40]. Adipokines are critical mediators of inflammation and metabolic balance [41]. For example, by encouraging T-cell activation, leptin contributes to enhancing immune responses and controlling appetite. However, adiponectin possesses anti-inflammatory qualities, and its levels are negatively correlated with obesity; slim people have higher quantities of adiponectin. Additionally, s adiponectin increases insulin sensitivity to protect against metabolic diseases.

Although adipokines potentially function in numerous ways, their impacts on the immune system can be grouped into two categories. The category that includes angiopoietin-like protein 2 (ANGPTL2), resistin, and leptin helps promote metabolic dysfunction and inflammation [42]. Leptin, in particular, links the nutritional state to immune function, as it is produced in greater amounts in individuals with obesity and contributes to chronic inflammation [43]. In contrast, the anti-inflammatory effects of adiponectin help counteract the negative impacts of leptin, making adiponectin a crucial factor in maintaining metabolic homeostasis in healthy individuals.

The other category of adipokines is anti-inflammatory and includes visfatin, adipsin, and adiponectin [44]. Changes in the levels of adipokines in these two categories are determined by the mass of adipose tissue and thus can be triggered by obesity. However, the actual functions of adipokines and nutrients in the immune system and metabolism are not clear.

Immune mechanism in adipose tissue during homeostasis

The interface between cells and tissues that store nutrients and the immune system has been researched broadly in VAT [45]. Although VAT lacks a barricade function, it is populated with an enormous number of immune cells even under quiescent conditions. Regulatory immune cells within adipose tissue are essential for maintaining tissue homeostasis because they mediate the balance between pro- and anti-inflammatory responses. For example, adipose tissue-resident macrophages (ATMs) exist in both the lean and people with obesity. In lean individuals, ATMs predominantly exhibit an anti-inflammatory M2 phenotype, which supports tissue repair and insulin sensitivity. However, in abdominal fat-tissue of people with obesity, these macrophages shift toward a proinflammatory M1 phenotype, contributing to chronic inflammation and metabolic dysfunction [46].

The availability of molecules such as interleukin (IL)-10 and IL-1Ra endows these immune cells with the anti-inflammatory capabilities of adiponectin [47]. As mentioned above, adipocytes are the core immune cell subtypes in VAT that are responsible for cellular immunity [48]. Furthermore, several dedicated immune cell subtypes are involved in adipose tissue homeostasis. VAT includes CD4 T cells, which form the largest cluster of cells, the majority of which are FoxP3-expressing supervisory T cells. IL-10, generated from regulatory T cells (Tregs), is instrumental in preventing inflammation in VAT [49]. Nonetheless, the loss of Tregs culminates in acute inflammation in VAT while enhancing the evolution of insulin resistance as a result of nutrient-aggravated obesity [50]. Another vital cluster of cells is invariant-chain natural killer T cells, which are responsible for regulating immune cell activities during homeostasis.

At the molecular level, adenosine monophosphate (AMP)-activated protein kinase (AMPK) maintains energy homeostasis during starvation and fasting [51]. Cellular stress from hypoxia contributes to an increase in the AMP/ATP ratio. AMP stimulates AMPK to restore energy levels by triggering the catabolism of the considerable quantity of fatty acids, glycolysis, autophagy [52], and the oxidation of fatty acids [53]. AMPK also prevents anabolic pathways such as gluconeogenesis and the synthesis of fatty acids, glycogen, and triglycerides [54].

Influence of nutrients on the immune system via adipose tissue

Good nutrition is useful in preventing malnutrition and noninfectious disorders. Because adipose tissue is the main nutrient storage area, nutrients significantly influence the phenotype of fat cells. High-fat and high-sugar diets promote inflammation in adipose tissue. Excess nutrients cause adipocyte hypertrophy and the infiltration of immune cells, especially macrophages. Obesity is associated with chronic low-grade inflammation, which is known to be a direct cause of type II diabetes and metabolic syndrome [55]. Owing to increased urbanization and lifestyle changes, the intake of energy, free sugar, salt, and fat is increasing [56]. Increased consumption of these nutrients is positively related to increases in adipose tissue, metabolic dysfunction, obesity, cellular oxidative stress, and other disorders [57].

However, nutrient-dense diets high in fiber, antioxidants, and polyunsaturated fats have anti-inflammatory effects on adipose tissue. These foods increase the production of adiponectin, an anti-inflammatory adipokine, while decreasing the infiltration of proinflammatory immune cells. As a result, proper nutrition is critical for modulating immunological responses within adipose tissue, which ultimately influences overall metabolic health.

Obesity-triggered changes in nutrient status are related to considerable increases in glucose and fatty acid levels. Diets rich in fatty acids inhibit the lipolytic role of adipocytes [58], whereas diets containing protein provide important amino acids for the synthesis of new proteins and the metabolism of lipids [59]. The composition and amount of protein in food affect metabolism in different ways [60]. In adipocytes, proteins prevent lipogenic enzymes, including glucose-6-phosphate dehydrogenase and fatty acid synthase [61].

Immune response of VAT to obesity

Obesity has a strong effect on the immune system. In both mice and humans, type II diabetes triggered by obesity is correlated with reduced levels of inflammatory mediators [62]. Obesity leads to an increase in proinflammatory ATMs in VAT, which transition from the M1 phenotype to the M2 phenotype [63]. In overweight individuals and people with type II diabetes, M1 ATMs promote chronic inflammation, which is considered a risk factor for the progression of insulin resistance. Although the cause of the increased accumulation of immune cells in fat tissue in individuals with obesity is not known, it is believed that leptin increases the accumulation of adipose tissue. Obesity stimulates the progression of an inflammatory reaction that impacts all aspects of the immune system [64]. The ultimate immune response is the cause of chronic inflammation and the major factor that induces several disorders in the population with obesity.

Starvation and the immune system

Starvation weakens the function of the immune system. Globally, starvation is one of the main health issues, as approximately 805 million individuals have insufficient food [65]. Unlike malnourished adults, most impacted children have a weakened immune system that increases their vulnerability to numerous diseases [66]. For this reason, malnutrition is the main cause of mortality in three million children annually. Both the innate and adaptive immune systems are suppressed by starvation. The production of key immune cells, such as T cells and neutrophils, is severely reduced by nutrient deficiency, leaving the body less well equipped to fight infection. In addition, malnourished individuals often experience decreased cytokine production and impaired macrophage and natural killer cell function, further compromising their immune defenses. Malnutrition can also cause thymic atrophy, which reduces the body’s ability to generate new T cells, thus weakening the overall immune response [67]. The physiological reaction to inadequate nutrients occurs in three stages.

During the fasting stage, the body is starved for several hours, and adipose lipolysis occurs to control fatty acid levels and empathic glycogenolysis to maintain blood glucose [68]. In the second stage, prolonged starvation occurs due to reduced glycogen stores. Afterward, the body switches to lipolysis to maintain energy; this process also produces glycerol and ketone bodies, the latter of which are used as fuel for organs [69]. This second phase lasts for several weeks, leading to significant weight loss. The third stage begins with considerable reductions in fat repositories and skeletal muscle to obtain amino acids for gluconeogenesis [70]. This state is associated with the loss of body mass and cannot be maintained for a long period. It is also characterized by decreased energy use, temperature, and immune function.

Impact of nutrients on bacterial flora

The bacterial flora, also known as the microbiome or gut flora, depends on the human body as a place to live. The bacterial flora promotes human health to support its own survival, a process called symbiosis. The important bacteria that live in the gastrointestinal tract are necessary for human health. A study conducted in 2004 provided the first evidence that the bacterial flora may play a notable role in the energy balance and thus the development of obesity [71]. In this study, germ-free mice were colonized with bacteria from the intestines of normal mice. At fourteen days, the initially germ-free mice showed a noteworthy 60% increase in body fat content, despite decreased food intake. This finding highlights the ability of the microbiome to influence fat storage and energy balance, suggesting that gut bacteria could regulate the efficiency of calorie absorption from the diet. Some types of bacteria are better at extracting energy from food and could result in increased fat storage even when food consumption is decreased. Furthermore, changes in dietary habits, such as consuming meals high in fat or sugar, affect the composition of the gut microbiota, which may encourage the growth of bacteria that support energy storage and contribute to obesity [72].

More intriguing is the follow-up study in which germ-free mice were colonized by bacterial flora from mice with obesity [73]. Compared with the 27% fat increase in the mice colonized with bacteria from lean mice, the body fat of the germ-free mice colonized with bacteria from mice with obesity increased by 47%. This finding suggests that the bacterial flora may have unappreciated links to body fat. Further research has demonstrated that the composition of gut bacteria can influence not only fat storage but also overall metabolism. Certain bacteria, such as Firmicutes, are more prevalent in individuals with obesity and are thought to be more efficient at breaking down complex carbohydrates into short-chain fatty acids, which are then absorbed as calories. In contrast, bacteria such as Bacteroidetes are more common in lean individuals and may play a role in limiting fat storage by promoting faster energy expenditure [74].

To identify whether the bacterial flora can predict weight status, scientists have evaluated the fecal microbiota of infants and compared it with weight conditions later in life [75]. Children who became children with obesity had fewer bifidobacteria in their bacterial flora during infancy and childhood than did children who maintained a healthy weight. Regardless of whether this connection is causal, it is clear that obesity is linked to specific of the bacterial flora.

Recently, studies have aimed to describe the bacterial flora and characterize it on the basis of metabolic profiles, such as energy-harvesting capacity, instead of traditional taxonomy (genus, species, and phylum) [76]. A controversial subject is whether it is important to group bacterial flora by metabolic traits for the purpose of determining a therapeutic approach to obesity. However, it is not clear whether the impact of diet on bacterial flora, the connections among bacterial floras, and health outcomes will become more apparent with a new classification scheme.

Obesity and leptin

Leptin is secreted by adipocytes and is thought to signal to the brain to prevent food intake and reduce weight [77]. This conclusion was reached based on the findings that rodents and humans lacking a functional leptin receptor or leptin itself show avid feeding and obesity. Thus, leptin treatment, especially leptin administration directly into the hypothalamus, is expected to significantly suppress dietary intake and lower fat stores and body weight in leptin-deficient animals [78]. Nevertheless, in most cases of people with obesity, leptin resistance occurs; in such cases, the individual has high circulating concentrations of leptin that are not sensed properly by the brain. Leptin resistance consequently disrupts the appropriate function of leptin, rending it unable to effectively regulate appetite or energy expenditure; hence, people with leptin resistance continue eating, resulting in obesity. There are three ways through which leptin resistance can develop: hypothalamic inflammation, high levels of free fatty acids, and problems related to leptin transport across the blood‒brain barrier. Thus, even in the presence of extremely high levels of leptin, its regulatory and downstream pathways do not tell the brain to reduce food intake and weight.

Nevertheless, the idea of leptin as an anti-obesity hormone has been questioned, as obesity is usually connected with high levels of leptin. In addition, humans and rodents who suffer from obesity due to a high-fat diet do not respond to leptin [79]. For example, in rodents, leptin is transported to the brain, binds to its receptor in the hypothalamus, and triggers JAK-STAT3 signaling, resulting in the destruction of orexigenic peptides and an increase in anorexigenic peptides. Although there is no clear dysfunction in leptin receptors in rodents with diet-induced obesity, transport of leptin across the blood‒brain barrier is decreased, and the level of SOCS3, an inhibitor of leptin signaling, is increased in the hypothalamus.

Leptin levels markedly decrease in response to fasting, suggesting substantial changes in energy balance and hormone levels [80]. Low leptin levels encourage overfeeding and the suppression of energy expenditure, immunity, and thyroid and reproductive hormone levels [81]. In rodents, low leptin levels increase orexigenic peptide levels and decrease anorexigenic peptide levels. Replenishment of leptin reverses these changes in hormone levels, metabolism, immunity, and hypothalamic neuropeptides. In addition, restoring leptin in patients without fat cells improves reproductive processes and reverses irregular glucose and lipid metabolism [82]. In an environment of plentiful food and limited exercise, this metabolic efficiency predisposes individuals toward obesity.