Open access peer-reviewed chapter
Abstract
Leptin, a hormone produced by fat cells, regulates energy balance and body weight by suppressing appetite and increasing energy expenditure. In obesity, there is often leptin resistance, reducing the hormone’s effects due to factors such as inflammation and changes in leptin receptors. This resistance leads to an increased risk of weight gain and obesity. Leptin therapy shows promise in treating obesity and related metabolic disorders, such as dyslipidemia and type 2 diabetes mellitus. It can lower body weight, improve insulin sensitivity, and reduce blood glucose and lipid levels. However, its effectiveness may be limited by the development of leptin resistance. Leptin also exhibits anti-inflammatory and cardiovascular protective effects, with potential therapeutic value for obesity-related conditions. Nevertheless, further research is necessary to comprehend leptin’s mechanisms and develop safe and effective therapies for these conditions, including those targeting dyslipidemia.
Keywords
- adipokines
- leptin receptors
- obesity
- lipid metabolism
- atherosclerosis
1. Introduction
Obesity, which is characterized by excessive body fat accumulation, is a major contributor to dyslipidemia. Leptin, a hormone secreted by adipose tissue, plays a crucial role in regulating energy balance, including appetite and metabolism.
Leptin resistance, a condition where the body is insensitive to leptin, is common in obesity, and it may contribute to dyslipidemia by altering lipid metabolism and promoting inflammation. Understanding the complex interplay between leptin, obesity, and dyslipidemia is crucial for developing effective strategies for the prevention and treatment of CVD. By elucidating the underlying mechanisms and pathways involved, researchers and clinicians can identify potential targets for intervention and develop personalized treatment plans for individuals with dyslipidemia and obesity.
1.1 Overview of obesity as a global epidemic
Obesity is a pandemic with potentially fatal effects on human health. Within the last 20 years, the prevalence of this condition has tripled globally, and it is still rising [1]. Studies have shown that obesity is influenced by genetics. It appears to be a polygenic condition based on the inheritance pattern, with minor contributions from several distinct genes, accounting for almost 25–70% of the variance in weight [2]. A BMI of >30 kg/m2 is measured as obese per the International Obesity Task Force and the WHO categorization [3]. The illness causes several systemic problems. The distribution of fat, rather than the total quantity of extra adipose tissue, appears to be significant for some of the consequences of obesity [4]. Additionally, obesity negatively impacts morbidity and death [5]. As its growing prevalence and importance are undeniable in today’s context, it would be worthwhile to discuss the various aspects of this disease.
Obesity is a medical condition characterized by an excessive accumulation of body fat that can have negative effects on health, including a shortened lifespan and increased health problems. It is classified as having a body weight that is at least 20% above the usual range. Overweight (pre-obesity) is defined as having a body mass index (BMI), which compares weight to height, between 25 and 30 kg/m2, while obesity is defined as having a BMI greater than 30 kg/m2. Overweight and obesity are characterized by abnormal or excessive deposits of fat that pose health risks. Hyperplastic obesity refers to an increase in the number of fat cells, while hypertrophic obesity refers to an increase in the size of fat cells, or a combination of both [1].
BMI is a statistical evaluation based on height and weight. The proportion of body fat is not measured, although it is thought to be beneficial for estimating healthy body weight. The BMI measurement can occasionally be deceiving; for example, a muscleman may have a high BMI yet have far less body fat than an unhealthy individual with a lower BMI. BMI serves as a useful indicator for the “typical person” in general. Body mass index, equal to weight in kg/height in m2, is the most often used measurement to assess obesity, despite not being a direct indicator of adiposity [6].
Classification of adults according to BMI:
Underweight<18.5
Normal range: 18.5–24.99
Overweight: >25
Pre obese: 25–29.99
Obese Class I: 30–34.99
Obese II: 35–39.99
Obese III: >40 [6]
Anthropometry (measures the thickness of skin folds), hydrodensitometry (underwater weighing), CT or MRI, and electrical impedance are additional methods for calculating obesity [7].
1.2 Definition and types of dyslipidemia
Dyslipidemia is a medical condition characterized by abnormal levels of lipids in the blood. It is a major risk factor for cardiovascular disease, including heart attacks and strokes [8].
There are several types of dyslipidemia, including:
High levels of low-density lipoprotein (LDL) cholesterol commonly referred to as “bad” cholesterol. LDL cholesterol can build up in the arteries, leading to plaque formation and narrowing of the blood vessels [9].
Low levels of high-density lipoprotein (HDL) cholesterol commonly referred to as “good” cholesterol. HDL cholesterol helps remove excess cholesterol from the blood vessels and carries it to the liver for processing [10].
High levels of triglycerides, which are another type of fat in the blood. High levels of triglycerides are often associated with low levels of HDL cholesterol and can increase the risk of cardiovascular disease [9].
Combined dyslipidemia, which refers to having high levels of both LDL cholesterol and triglycerides and low levels of HDL cholesterol.
Dyslipidemia can be caused by several factors, including genetics, lifestyle factors such as diet and exercise, and certain medical conditions such as diabetes and hypothyroidism [8]. Treatment options for dyslipidemia include lifestyle modifications such as diet and exercise, as well as medications such as statins and fibrates [8].
1.3 Importance of leptin in energy balance and metabolism
Leptin, discovered in 1994, is a hormone that plays a key role in regulating energy balance and body weight [11]. It acts on the hypothalamus to suppress appetite and increase energy expenditure [12]. Leptin also influences lipid metabolism, including synthesis, storage, and transport [13]. By binding to receptors in the hypothalamus, leptin signals the brain about the body’s fat stores and helps regulate food intake and energy expenditure [14, 15]. High leptin levels reduce food intake and increase energy expenditure, while low levels stimulate hunger and conserve energy [12]. Leptin also increases energy expenditure by activating the sympathetic nervous system [16]. Moreover, it enhances insulin sensitivity and glucose metabolism, reducing the risk of insulin resistance and diabetes [17]. Dysregulation of leptin signaling can contribute to obesity and metabolic disorders [14].
1.4 Significance of leptin resistance in obesity
Leptin resistance is a condition where cells become less responsive to the hormone leptin, resulting in an inability to regulate appetite and energy balance effectively [18]. In obesity, adipose tissue produce elevated levels of leptin, which should decrease appetite and increase energy expenditure to reduce body weight. However, many obese individuals experience inadequate brain response to increased leptin, leading to improper regulation of appetite and energy balance, known as leptin resistance [19].
Leptin resistance in obesity is believed to be caused by several factors, including chronic inflammation, insulin resistance, and changes in the hypothalamus and other brain regions that regulate appetite and energy balance. These factors can lead to a disruption in leptin signaling [20].
Leptin resistance can be a vicious cycle in obesity, as higher levels of fat stores lead to increased leptin production, which should reduce appetite and increase energy expenditure [21]. However, when leptin resistance occurs, the body fails to respond appropriately to the increased leptin levels, leading to continued overeating and reduced energy expenditure, contributing to further weight gain and worsening of the condition [22].
2. Leptin: physiology and mechanisms
2.1 Role of leptin in regulating appetite, energy expenditure, and metabolism
Leptin plays a crucial role in regulating appetite, energy expenditure, and metabolism.
Leptin resistance, which occurs when the body becomes insensitive to the effects of leptin, can disrupt the balance of appetite, energy expenditure, and metabolism. This can lead to obesity, metabolic syndrome, and other health problems [23, 24].
2.2 Leptin signaling pathway and its effects on lipid metabolism
The leptin signaling pathway begins with the binding of leptin to its receptor, which is located on the surface of cells in the hypothalamus and other parts of the body. When leptin binds to its receptor, it activates a cascade of signaling molecules that transmit the signal into the cell, resulting in various physiological effects [25].
One of the main effects of leptin on lipid metabolism is the promotion of lipolysis, which is the breakdown of stored fat in adipose tissue. Leptin stimulates lipolysis by activating an enzyme called hormone-sensitive lipase (HSL), which breaks down triglycerides (stored fat) into free fatty acids and glycerol. The free fatty acids can then be used as a source of energy by other tissues in the body [26].
Leptin also affects lipid metabolism by regulating the expression of genes involved in lipid synthesis and storage. It inhibits the expression of genes involved in fatty acid synthesis, such as fatty acid synthase (FAS), and stimulates the expression of genes involved in fatty acid oxidation, such as carnitine palmitoyltransferase-1 (CPT-1). This results in a shift towards fat burning and away from fat storage [27].
Furthermore, leptin signaling affects the activity of several transcription factors, including peroxisome proliferator-activated receptor gamma (PPAR-gamma) and sterol regulatory element-binding protein-1c (SREBP-1c), which are key regulators of lipid metabolism. Leptin inhibits the activity of PPAR-gamma, which promotes fat storage, and stimulates the activity of SREBP-1c, which promotes fatty acid oxidation [28].
Leptin signaling pathway plays a crucial role in regulating lipid metabolism by promoting lipolysis, inhibiting fatty acid synthesis, and stimulating fatty acid oxidation. These effects help to maintain energy balance and prevent the development of metabolic disorders such as obesity and type 2 diabetes mellitus [29].
2.3 Leptin receptors and mechanisms of leptin action
Leptin, a hormone involved in metabolism and energy homeostasis, exerts its effects on various tissues throughout the body through specific mechanisms of action mediated by leptin receptors. The distribution of leptin receptors reflects the diverse effects of leptin on different tissues and highlights its crucial role in maintaining overall health and wellness [30, 31]. Leptin receptors are proteins that are expressed on the surface of various cells in the body and are responsible for binding and responding to the hormone leptin. There are six different isoforms of leptin receptors, which are generated by alternative splicing of the gene encoding the receptor. These isoforms differ in their length and structure, and some have different affinities for leptin [32].
In adipose tissue, leptin regulates the synthesis and release of adipokines, which are signaling molecules involved in metabolic processes such as inflammation and insulin sensitivity. Leptin also activates hormone-sensitive lipase (HSL), promoting lipolysis—the breakdown of stored fat into free fatty acids and glycerol. These fatty acids are then released into the bloodstream for energy production [11].
In the liver, leptin inhibits glucose synthesis and promotes the breakdown of stored glycogen. It also suppresses the synthesis of fatty acids and triglycerides, thus reducing the risk of fatty liver disease (hepatic steatosis) [33].
Leptin plays a role in skeletal muscle by promoting glucose uptake and metabolism. It activates AMP-activated protein kinase (AMPK), which increases glucose uptake and energy production in muscle cells. This process helps improve insulin sensitivity [34].
In the pancreas, leptin inhibits insulin secretion from pancreatic beta cells. By reducing insulin levels in the bloodstream, leptin helps prevent hyperinsulinemia and improves insulin sensitivity in peripheral tissues [35].
Leptin’s action in the brain primarily occurs in the hypothalamus, where it regulates appetite, energy expenditure, and metabolism. Leptin suppresses the release of appetite-stimulating neuropeptide Y (NPY) and agouti-related peptide (AgRP), while stimulating the release of appetite-suppressing proopiomelanocortin (POMC) and cocaine-and-amphetamine-regulated transcript (CART). Additionally, leptin increases the activity of brown adipose tissue and promotes thermogenesis, thereby enhancing energy expenditure [36].
Overall, leptin’s effects on specific tissues are mediated by leptin receptors, which are expressed in adipose tissue, liver, skeletal muscle, pancreas, and the hypothalamus of the brain. By understanding these tissue-specific mechanisms of action, we can better appreciate the role of leptin in regulating metabolism and maintaining energy balance.
3. Obesity: causes and risk factors
3.1 Causes for obesity
It is critical to pinpoint the causes of any medical illness to comprehend it properly. Obesity has a wide variety of underlying causes. These consist of the following [37]:
Gender: Women are more prone to weight gain than men, potentially due to factors such as a slower metabolic rate and postmenopausal metabolic rate decline. Retaining weight gained during pregnancy is another contributing factor.Heredity: Obesity can run in families, suggesting a genetic contribution. Having an obese or overweight mother increases the risk of developing obesity. Genetic factors influence energy intake, expenditure, and susceptibility to obesity.Genetics of obesity: Carrying two copies of the FTO gene is associated with higher body weight and increased risk of obesity. The heritability of obesity varies, and polymorphisms in multiple genes can affect appetite and metabolism.Unhealthy eating habits: Regular consumption of a high-fat diet and junk food, large meals, and irregular eating schedules contribute to obesity. The relationship between fast food consumption and obesity is prominent.Excessive calorie intake: Overeating is prevalent worldwide, contributing to obesity. The proportion of obese adults has significantly increased over time.Malnutrition: Childhood malnutrition followed by the availability of additional dietary energy can promote fat accumulation. Certain foods and endocrine disruptors can alter lipid metabolism.Endocrine disorders: Certain endocrine disorders, such as growth hormone insufficiency, Cushing’s disease, and hypothyroidism, can cause obesity.Sedentary lifestyle: Lack of physical activity and modern conveniences that reduce the need for physical exertion contribute to obesity. Reduced levels of physical activity in children and adults are concerning.Psychological factors: Emotional eating as a coping mechanism, binge eating due to depression, and stress-induced overeating contribute to obesity. Sleep deprivation is also a factor.Psychiatric illness: Eating disorders and specific mental conditions increase the risk of obesity.Medications: Some medications, such as insulin, antidepressants, steroids, and hormonal contraceptives, may lead to weight gain or body composition changes.
3.2 Risk factors for obesity
Some people develop a susceptibility to fat via no fault of their own. Several risk factors increase the chances of becoming obese. These consist of the following [1]:
Family history: Heredity can play a role in obesity, but it is not solely due to genetics. Family eating habits and lifestyle choices can also contribute to the tendency for obesity to run in families. Children of two obese parents have a much higher risk of being obese.Side effects of quitting smoking: Some individuals may experience weight gain after quitting smoking, contributing to obesity. Former smokers may gain several pounds per week after quitting, with an average weight gain of 4 to 10 pounds in the first six months.
3.3 Pathophysiology of obesity
Obesity arises from an imbalance between energy intake and expenditure influenced by behavioral and physiological factors [38]. The surge in obesity rates in Western countries is primarily attributed to changing environmental conditions, including decreased exercise and possibly increased food intake [39]. Factors such as increased calorie intake, reduced energy expenditure, or a combination of both can contribute to obesity.
While sedentary behavior is believed to contribute to weight gain, more research is needed to establish this link conclusively [40]. Physical activity involvement tends to decline with age, with a higher percentage of women than men reporting insufficient exercise in each age group [41]. Other variables associated with being overweight include age, race, gender, and socioeconomic status, although the reasons for these associations are not fully understood [42]. The high heritability of body mass index suggests that genetics play a significant role in obesity [43]. The genetics and the environment contribute to 30 to 40% and 60 to 70% of the variance in BMI, respectively [44]. Genetic factors may interact with environmental conditions, such as high-fat diets and a sedentary lifestyle, to increase the risk of obesity [45].
Metabolic syndrome and fat intake are positively correlated, with high levels of cholesterol, saturated fat, and sugar commonly found in Western diets. Fatty acids and cholesterol have been linked to pro-inflammatory signaling cascades in cultured macrophages [46]. Genetic mutations in the pro-opiomelanocortin (POMC) gene can result in severe obesity by impairing the synthesis of Alpha-melanocyte-stimulating hormone (α-MSH), a neuropeptide that reduces hunger. Mutations in the proenzyme convertase 1 (PC-1) gene can also hinder the synthesis of α-MSH from its precursor peptide, POMC. The type 4 melanocortin receptor (MC4R) binds to α-MSH and plays a role in preventing overeating. Loss-of-function mutations in this receptor can contribute to extreme obesity in some individuals [47, 48, 49]. Leptin and its receptors are involved in regulating appetite and weight through the enhancement of α-MSH and POMC [50]. The environment plays a significant role in obesity, regardless of genetic predisposition, as evidenced by famine preventing obesity in susceptible individuals [50].
The lipostat regulatory system, which involves signals from energy stores compared to targets in the brain, determines food intake, activity levels, and metabolism. Some obese individuals may have excessively high lipostats, leading to excessive body weight. The concept of a body weight “set point” is supported by physiological mechanisms involving an adipostat receptor in the hypothalamus and a sensing system in adipose tissue that reflects fat storage [51]. The adipostat signal influences appetite and energy expenditure based on the body’s fat reserves [52]. Leptin, produced by the Ob gene, and leptin receptors produced by the db gene are involved in this physiological regulation [11].
Hormones such as ghrelin, cholecystokinin, insulin, adiponectin, orexin, peptide YY (PYY 3–36) and other mediators play a role in hunger control, adipose tissue storage patterns, and the development of insulin resistance [53]. Adipokines, which are mediators produced by adipose tissue, are believed to influence various disorders associated with obesity [54]. Leptin, primarily released by adipose cells, acts on the brain and regulates long-term hunger. Ghrelin and leptin work in concert to impact short-term and long-term hunger signals [55, 56, 57].
Leptin and ghrelin specifically target the hypothalamus, a key brain region involved in hunger regulation. The melanocortin pathway in the hypothalamus, particularly the arcuate nucleus, plays a crucial role in controlling satiety and appetite. Neurons in the arcuate nucleus express agouti-related peptide/neuropeptide-Y (AgRP/NPY) and POMC cocaine-and-amphetamine-regulated-transcript (POMC/CART), with the former promoting feeding and the latter promoting satiety [58, 59, 60]. Leptin stimulates the POMC/CART neurons while inhibiting the AgRP/NPY neurons, contributing to the regulation of food intake. Leptin deficiency or resistance can lead to increased food intake and may contribute to certain forms of obesity [61].
3.4 Metabolic abnormalities associated with obesity, including dyslipidemia
Obesity is a complex metabolic disorder that is associated with several metabolic abnormalities, including dyslipidemia. Dyslipidemia is a condition characterized by abnormal levels of lipids (fats) in the blood, including high levels of low-density lipoprotein (LDL) cholesterol (commonly referred to as “bad” cholesterol), low levels of high-density lipoprotein (HDL) cholesterol (commonly referred to as “good” cholesterol), and high levels of triglycerides [62].
In obesity, the accumulation of excess fat in adipose tissue leads to dyslipidemia through several mechanisms. First, adipose tissue secretes pro-inflammatory cytokines and hormones, such as leptin and adiponectin, which can promote inflammation and insulin resistance. Insulin resistance can lead to increased production of very-low-density lipoprotein (VLDL) in the liver, which can contribute to increased levels of triglycerides in the blood [63].
Additionally, excess adipose tissue can lead to an increased production of LDL cholesterol particles and a decrease in HDL cholesterol levels. This can lead to the formation of atherosclerotic plaques in the blood vessels, increasing the risk of cardiovascular disease [64].
Obesity is also associated with changes in the gut microbiome, which can contribute to dyslipidemia. Changes in the gut microbiome can lead to an increase in the production of bile acids, which can contribute to increased cholesterol absorption in the gut [65].
Furthermore, obesity is often associated with a sedentary lifestyle and unhealthy dietary habits, such as a high intake of saturated and trans fats, which can contribute to dyslipidemia [64].
Dyslipidemia is a significant risk factor for cardiovascular disease, including heart attacks and strokes. Therefore, management of dyslipidemia is an important component of obesity treatment. Treatment options for dyslipidemia include lifestyle modifications such as diet and exercise, as well as medications such as statins and fibrates, which can help to lower LDL cholesterol levels and increase HDL cholesterol levels [64].
3.5 Role of adipose tissue in obesity-related metabolic dysregulation
Adipose tissue is a key component in the development of obesity-related metabolic dysfunctions. In obesity, the adipose tissue becomes dysfunctional, leading to chronic inflammation, insulin resistance, and dyslipidemia. One of the primary functions of adipose tissue is to store excess energy in the form of triglycerides. When the energy intake exceeds energy expenditure, the adipose tissue expands to accommodate the excess energy. In obesity, this expansion can lead to adipose tissue dysfunction, characterized by hypertrophy (increase in adipocyte size) and hyperplasia (increase in adipocyte number) [66].
Adipose tissue dysfunction can lead to the release of pro-inflammatory cytokines, such as TNF-alpha and IL-6, which can promote inflammation and insulin resistance. Insulin resistance occurs when cells become less responsive to insulin, leading to a decrease in glucose uptake and metabolism. This can lead to high blood sugar levels and eventually to the development of type 2 diabetes [67].
Furthermore, adipose tissue can release free fatty acids into the bloodstream, which can contribute to dyslipidemia. Free fatty acids can lead to an increase in triglycerides and LDL cholesterol levels, while also decreasing HDL cholesterol levels [68].
Additionally, adipose tissue produces several hormones, such as leptin and adiponectin, which can influence appetite and metabolism. Leptin, which is produced by adipocytes, regulates appetite and energy expenditure by signaling to the hypothalamus in the brain. However, in obesity, the body can become resistant to leptin, leading to a failure to regulate appetite and energy expenditure properly [52]. Adiponectin, on the other hand, plays a role in insulin sensitivity and glucose metabolism. In obesity, the production of adiponectin is often decreased, leading to a decrease in insulin sensitivity and an increase in blood sugar levels [69].
Overall, adipose tissue dysfunction plays a significant role in the development of obesity-related metabolic dysfunctions. Treatment strategies for obesity-related metabolic dysfunctions often involve lifestyle modifications, such as diet and exercise, as well as pharmacological interventions that target adipose tissue function and inflammation [70].
3.6 Overview of the concept of adipokines and their role in obesity
Adipokines are a group of bioactive molecules that are secreted by adipose tissue and play an important role in the regulation of energy metabolism, inflammation, and immune function. Adipokines can have both pro-inflammatory and anti-inflammatory effects, depending on the specific adipokine and the context in which it is secreted [71].
In obesity, adipose tissue becomes dysfunctional, leading to alterations in the secretion of adipokines. Dysregulated adipokine secretion can contribute to the development of obesity-related metabolic disorders, such as insulin resistance, dyslipidemia, and cardiovascular disease [72]. Leptin is one of the most well-known adipokines and is primarily secreted by adipocytes [18].
Adiponectin is another important adipokine that plays a role in insulin sensitivity and glucose metabolism. Adiponectin levels are typically decreased in obesity, contributing to insulin resistance and an increase in blood sugar levels [73]. Other adipokines, such as TNF-alpha, IL-6, and resistin, have been implicated in the development of inflammation and insulin resistance in obesity [74, 75]. TNF-alpha and IL-6 are pro-inflammatory cytokines that are secreted by adipose tissue and can contribute to the development of chronic inflammation, while resistin has been shown to impair insulin signaling [75]. On the other hand, adipokines such as omentin, visfatin, and adipolin have been shown to have anti-inflammatory effects and can improve insulin sensitivity [76].
Overall, the dysregulated secretion of adipokines in obesity plays a critical role in the development of metabolic dysfunctions. Understanding the mechanisms by which adipokines contribute to obesity-related disorders can help in the development of new therapeutic strategies for the prevention and treatment of obesity and its associated complications [66].
4. Dyslipidemia: pathophysiology and consequences
4.1 Pathophysiology of dyslipidemia, including the role of lipoproteins
Dyslipidemia is a common metabolic disorder characterized by an abnormal level of lipids (cholesterol and triglycerides) in the blood. It is a major risk factor for the development of cardiovascular disease, which remains the leading cause of morbidity and mortality worldwide. The pathophysiology of dyslipidemia is complex and involves an imbalance in the production and clearance of lipoproteins [9].
Lipoproteins are complexes of lipids and proteins that play a critical role in the transport of lipids in the bloodstream. They are classified into several types based on their density and size. The main types of lipoproteins include chylomicrons, very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL) [77].
Chylomicrons are formed in the intestine and transport dietary triglycerides to the liver and peripheral tissues [78]. VLDL is synthesized in the liver and transports endogenous triglycerides to peripheral tissues [79]. IDL is a remnant of VLDL metabolism, and LDL is a remnant of IDL metabolism. LDL is often referred to as “bad” cholesterol because it can accumulate in the arterial wall and contribute to the development of atherosclerosis, a condition characterized by the buildup of plaque in the arteries. In contrast, HDL is often referred to as “good” cholesterol because it can remove excess cholesterol from peripheral tissues and transport it to the liver for elimination [80].
The pathophysiology of dyslipidemia involves an imbalance in the production and clearance of lipoproteins [81]. In insulin resistance and obesity, the liver produces an excess of VLDL, leading to elevated triglycerides in the blood. Elevated VLDL can also lead to an increase in LDL levels as VLDL is converted to LDL [82]. In addition to the overproduction of VLDL, dyslipidemia can also be caused by a decrease in LDL clearance. LDL particles can become modified, making them more prone to accumulate in the arterial wall and contribute to the development of atherosclerosis [83].
HDL levels are also affected in dyslipidemia. In insulin resistance and obesity, there is a decrease in HDL levels, which can contribute to the development of atherosclerosis [84]. HDL can become dysfunctional, losing its ability to remove excess cholesterol from peripheral tissues [85]. Overall, the dysregulation of lipoprotein metabolism in dyslipidemia plays a critical role in the development of atherosclerosis and cardiovascular disease [77].
Dyslipidemia is a complex metabolic disorder that is characterized by an abnormal level of lipids in the blood [86]. Lipoproteins, which are complexes of lipids and proteins, play a critical role in the transport of lipids in the bloodstream [78]. The pathophysiology of dyslipidemia involves an imbalance in the production and clearance of lipoproteins, leading to the accumulation of lipids in the arterial wall and the development of atherosclerosis [87]. Understanding the role of lipoproteins in dyslipidemia can help in the development of new therapeutic strategies for the prevention and treatment of cardiovascular disease [88].
4.2 Consequences of dyslipidemia on cardiovascular health, liver function, and other organs
Dyslipidemia is a significant risk factor for the development of cardiovascular disease, which remains the leading cause of morbidity and mortality worldwide. The consequences of dyslipidemia on cardiovascular health, liver function, and other organs are numerous and can be severe.
4.3 Importance of managing dyslipidemia in the context of overall health
The management and prevention of dyslipidemia involve lifestyle modifications, such as a healthy diet, regular exercise, weight loss, and smoking cessation. Medications, such as statins, fibrates, niacin, and cholesterol absorption inhibitors, are also commonly used to lower lipid levels in the blood. The treatment of dyslipidemia can reduce the risk of cardiovascular disease and improve liver function, kidney function, and other organ health.
Dyslipidemia is a significant risk factor for the development of cardiovascular disease, liver disease, and other health complications. The consequences of dyslipidemia on cardiovascular health, liver function, and other organs can be severe and life-threatening. The management and prevention of dyslipidemia involve lifestyle modifications and medications. Early detection and treatment of dyslipidemia can reduce the risk of cardiovascular disease and improve overall health outcomes.
5. Leptin and dyslipidemia: mechanisms and interactions
5.1 Impact of leptin on lipid metabolism, including lipogenesis, lipolysis, and fatty acid oxidation
Leptin acts on various tissues in the body, including the liver, muscle, and adipose tissue, to influence lipid metabolism.
Impact of leptin on lipogenesis: Leptin inhibits lipogenesis, the process of synthesizing new fatty acids from glucose. Leptin accomplishes this by suppressing the activity of enzymes that are involved in the synthesis of fatty acids, such as acetyl-CoA carboxylase and fatty acid synthase. Leptin also increases the activity of enzymes that are involved in the breakdown of fatty acids, such as hormone-sensitive lipase, thereby promoting lipolysis [97].Impact of leptin on lipolysis: Leptin promotes lipolysis, the process of breaking down triglycerides in adipose tissue into fatty acids and glycerol. Leptin accomplishes this by activating hormone-sensitive lipase, an enzyme that is involved in the breakdown of triglycerides in adipose tissue. The resulting increase in circulating fatty acids can be used as a source of energy by various tissues in the body, including muscle and liver [98].Impact of leptin on fatty acid oxidation: Leptin also promotes fatty acid oxidation, the process of using fatty acids as a source of energy. Leptin accomplishes this by increasing the expression of genes involved in fatty acid oxidation, such as peroxisome proliferator-activated receptor alpha (PPARα) and carnitine palmitoyltransferase I (CPT1). PPARα is a transcription factor that regulates the expression of genes involved in fatty acid oxidation, while CPT1 is an enzyme that transports fatty acids into the mitochondria, where they can be oxidized for energy production [99].
In summary, leptin plays a critical role in lipid metabolism by inhibiting lipogenesis, promoting lipolysis, and increasing fatty acid oxidation. Dysregulation of leptin signaling can contribute to the development of dyslipidemia, obesity, and related metabolic disorders. Understanding the impact of leptin on lipid metabolism may lead to the development of new therapies for the treatment of metabolic disorders.
5.2 Leptin’s role in regulating hepatic lipid metabolism
Leptin acts on the liver to influence lipid metabolism, including lipogenesis, lipolysis, and fatty acid oxidation.
Role of leptin in hepatic lipogenesis: Leptin inhibits hepatic lipogenesis, the process of synthesizing new fatty acids from glucose. Leptin accomplishes this by suppressing the activity of enzymes that are involved in the synthesis of fatty acids, such as acetyl-CoA carboxylase and fatty acid synthase [100]. In addition, leptin also reduces the expression of sterol regulatory element-binding protein 1c (SREBP-1c), a transcription factor that regulates the expression of genes involved in lipogenesis [18].Role of leptin in hepatic lipolysis: Leptin promotes hepatic lipolysis, the process of breaking down triglycerides stored in the liver into fatty acids and glycerol. Leptin accomplishes this by activating hormone-sensitive lipase, an enzyme that is involved in the breakdown of triglycerides in adipose tissue [11]. The resulting increase in circulating fatty acids can be used as a source of energy by various tissues in the body, including the liver.Role of leptin in hepatic fatty acid oxidation: Leptin also promotes hepatic fatty acid oxidation, the process of using fatty acids as a source of energy. Leptin accomplishes this by increasing the expression of genes involved in fatty acid oxidation, such as peroxisome proliferator-activated receptor alpha (PPARα) and carnitine palmitoyltransferase I (CPT1). PPARα is a transcription factor that regulates the expression of genes involved in fatty acid oxidation, while CPT1 is an enzyme that transports fatty acids into the mitochondria, where they can be oxidized for energy production [100].
Leptin resistance, a condition where the body is resistant to the effects of leptin, is associated with dysregulation of hepatic lipid metabolism. In individuals with leptin resistance, the liver may continue to produce and store fatty acids, leading to the development of hepatic steatosis, a condition characterized by the accumulation of fat in the liver [101]. Over time, hepatic steatosis can progress to nonalcoholic steatohepatitis (NASH), a more severe form of liver disease that can lead to liver fibrosis, cirrhosis, and hepatocellular carcinoma [102].
Leptin plays an essential role in regulating hepatic lipid metabolism by inhibiting lipogenesis, promoting lipolysis, and increasing fatty acid oxidation [103]. Dysregulation of leptin signaling can contribute to the development of hepatic steatosis and related liver disorders. Understanding the impact of leptin on hepatic lipid metabolism may lead to the development of new therapies for the treatment of liver diseases [104].
5.3 Influence of leptin resistance on lipid metabolism and dyslipidemia
Leptin resistance is a condition where the body is less sensitive to the effects of leptin. It is commonly seen in individuals with obesity and is thought to contribute to the development of dyslipidemia, a condition characterized by abnormal levels of lipids in the blood [105]. Leptin resistance can lead to dysregulation of lipid metabolism in several ways.
Firstly, leptin resistance can result in increased lipogenesis, the process of synthesizing new fatty acids from glucose. This is because leptin normally inhibits lipogenesis in the liver, but when leptin resistance occurs, this inhibitory effect is diminished [106]. As a result, the liver may continue to produce and store fatty acids, leading to the development of dyslipidemia.
Secondly, leptin resistance can contribute to decreased lipolysis, the process of breaking down stored triglycerides into fatty acids and glycerol. Leptin normally promotes lipolysis by activating hormone-sensitive lipase, an enzyme involved in the breakdown of stored triglycerides. However, when leptin resistance occurs, this activation is reduced, leading to decreased breakdown of stored triglycerides and a buildup of triglycerides in the blood [107].
Thirdly, leptin resistance can lead to decreased fatty acid oxidation, the process of using fatty acids as a source of energy. Leptin normally promotes fatty acid oxidation by increasing the expression of genes involved in fatty acid oxidation, such as peroxisome proliferator-activated receptor alpha (PPARα) and carnitine palmitoyl transferase I (CPT1). However, when leptin resistance occurs, this up regulation is reduced, leading to decreased fatty acid oxidation and a buildup of fatty acids in the blood [108]. All of these changes in lipid metabolism can contribute to the development of dyslipidemia, including increased levels of triglycerides, LDL cholesterol, and decreased levels of HDL cholesterol. Dyslipidemia is a major risk factor for cardiovascular disease, and therefore, leptin resistance can increase the risk of developing cardiovascular disease.
Leptin resistance is a condition that is commonly seen in individuals with obesity and can contribute to dyslipidemia by affecting lipid metabolism in several ways. Understanding the role of leptin resistance in dyslipidemia may lead to the development of new therapies for the treatment of dyslipidemia and its associated cardiovascular risks [75].
5.4 Interactions between leptin and other adipokines in the context of dyslipidemia
Leptin has been shown to interact with several other adipokines, including adiponectin, resistin, and visfatin [109]. Adiponectin is a protein hormone that is also secreted by adipose tissue and is known to have insulin-sensitizing and anti-inflammatory effects. Adiponectin has been shown to improve lipid metabolism by increasing fatty acid oxidation and decreasing lipogenesis. Additionally, adiponectin has been shown to inhibit the formation of foam cells, which are a key component of atherosclerotic plaques that contribute to the development of cardiovascular disease [110]. Leptin has been shown to have an inhibitory effect on adiponectin production, which may contribute to the dysregulation of lipid metabolism seen in individuals with leptin resistance [111].
Resistin is another adipokine that has been implicated in the development of dyslipidemia. Resistin is thought to contribute to the development of insulin resistance and dyslipidemia by decreasing insulin sensitivity and increasing lipolysis. Leptin has been shown to have a stimulatory effect on resistin production, which may further exacerbate the effects of resistin on lipid metabolism [112, 113].
Visfatin, also known as nicotinamidephosphoribosyltransferase (NAMPT), is another adipokine that has been shown to play a role in the regulation of lipid metabolism. Visfatin has been shown to increase lipolysis and decrease fatty acid oxidation, which can contribute to the development of dyslipidemia. Leptin has been shown to have a stimulatory effect on visfatin production, which may further contribute to the dysregulation of lipid metabolism seen in individuals with leptin resistance [114].
Interactions between leptin and other adipokines, such as adiponectin, resistin, and visfatin, are thought to play an important role in the development of dyslipidemia. Dysregulation of these interactions, particularly in the context of leptin resistance, may contribute to the development of dyslipidemia and its associated cardiovascular risks. Understanding the complex interplay between these adipokines may lead to the development of new therapies for the treatment of dyslipidemia and its associated complications.
6. Clinical implications and management
6.1 Clinical significance of leptin and dyslipidemia in obesity-related health outcomes
Leptin and dyslipidemia are two important factors that are associated with obesity-related health outcomes, and their clinical significance cannot be overstated. Leptin, as a hormone that is secreted by adipose tissue, plays a key role in regulating energy metabolism and appetite. In obesity, however, individuals often develop a resistance to leptin, which can lead to dysregulation of energy balance and metabolic dysfunction. This can lead to a range of health outcomes, including insulin resistance; type 2 diabetes mellitus, and cardiovascular disease [64, 75, 77, 90].
Dyslipidemia, on the other hand, refers to abnormalities in lipid metabolism, including elevated levels of cholesterol and triglycerides. Obesity is a major risk factor for dyslipidemia, as excess adipose tissue can lead to increased production of triglycerides and decreased clearance of cholesterol. Dyslipidemia can lead to the development of atherosclerosis and cardiovascular disease, which are major causes of morbidity and mortality in individuals with obesity [9, 10, 87, 88].
The clinical significance of leptin and dyslipidemia in obesity-related health outcomes can be seen in numerous studies [115, 116, 117]. For example, studies have shown that individuals with leptin resistance are at increased risk of developing type 2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease. Similarly, dyslipidemia has been linked to an increased risk of cardiovascular disease and other metabolic disorders in individuals with obesity [64, 70].
Treatment of leptin resistance and dyslipidemia is an important aspect of managing obesity-related health outcomes. Lifestyle modifications, such as dietary changes and increased physical activity, can improve both leptin resistance and dyslipidemia [118]. Medications, such as statins for dyslipidemia and leptin sensitizers for leptin resistance, may also be used in some cases [119, 120].
Leptin and dyslipidemia are both clinically significant factors in obesity-related health outcomes. Understanding their role in the development of metabolic dysfunction and cardiovascular disease is important in developing effective prevention and treatment strategies for individuals with obesity [121].
6.2 Diagnostic evaluation and assessment of dyslipidemia in the context of leptin and obesity
The diagnostic evaluation and assessment of dyslipidemia in the context of leptin and obesity typically involves a combination of clinical evaluation, laboratory testing, and imaging studies.
Clinical evaluation may include a detailed medical history and physical examination, which can help identify risk factors for dyslipidemia and cardiovascular disease. This may include a history of obesity, diabetes, hypertension, and family history of cardiovascular disease.
Laboratory testing is also an important component of the diagnostic evaluation for dyslipidemia. This typically includes a lipid profile, which measures levels of total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides in the blood. In individuals with obesity and/or leptin resistance, these levels may be elevated [122].
Imaging studies, such as computed tomography (CT) or magnetic resonance imaging (MRI), may also be used to assess the extent of fatty infiltration in the liver, which is a common complication of dyslipidemia in the context of obesity and leptin resistance [123].
In addition to these standard tests, assessment of leptin levels and leptin resistance may also be considered in individuals with obesity and dyslipidemia. This may involve measurement of circulating leptin levels, as well as assessment of leptin receptor expression and signaling in adipose tissue [105].
Overall, the diagnostic evaluation and assessment of dyslipidemia in the context of leptin and obesity should be tailored to the individual patient and may involve a multidisciplinary approach involving primary care physicians, endocrinologists, and cardiologists. The goal of this evaluation is to identify and address underlying metabolic dysfunctions in order to prevent or manage complications such as cardiovascular disease and non-alcoholic fatty liver disease.
6.3 Management approaches for dyslipidemia in obese individuals
The management of dyslipidemia in obese individuals typically involves a combination of lifestyle modifications, pharmacotherapy, and bariatric surgery, depending on the severity of the dyslipidemia and the presence of other risk factors for cardiovascular disease.
It is important to note that the management of dyslipidemia in obese individuals should be individualized and tailored to the specific needs and medical history of the patient. Close monitoring of lipid levels, as well as any potential side effects of medications, is also important in ensuring effective management of dyslipidemia in this population.
7. Future directions and emerging therapies targeting leptin and dyslipidemia in obesity
Leptin and dyslipidemia are both complex metabolic conditions that are closely related to obesity. While current treatments, including lifestyle modifications, pharmacotherapy, and bariatric surgery, can be effective in managing dyslipidemia in obese individuals, emerging therapies targeting leptin and dyslipidemia hold promise for improving outcomes [126]. One potential approach involves targeting leptin resistance directly. Leptin sensitizers, such as the drug metreleptin, have been shown to improve insulin sensitivity and lipid metabolism in patients with leptin deficiency [127]. More research is needed to determine whether these drugs could be effective in treating leptin resistance in obese individuals.
Another approach involves targeting specific adipokines that play a role in dyslipidemia. For example, the drug adipotide, which targets the adipokine adiponectin, has been shown to reduce body weight and improve insulin sensitivity in animal models. Clinical trials are currently underway to determine whether adipotide could be effective in treating obesity-related conditions in humans [128].
Other emerging therapies include gene therapy, stem cell therapy, and microbiome-based therapies. Gene therapy approaches involving the introduction of genes regulating lipid metabolism into adipose tissue are being explored. These strategies aim to address dyslipidemia in obesity by directly targeting adipose tissue. Further research is needed to evaluate the efficacy and safety of gene therapy in managing dyslipidemia [129]. Stem cell therapy may involve using stem cells to regenerate healthy adipose tissue or to promote lipid metabolism. This approach aims to address dyslipidemia in obesity by leveraging the regenerative capabilities of stem cells [130]. Microbiome-based therapies, which involve manipulating the gut microbiota, have shown promise in promoting healthy lipid metabolism. These approaches seek to modulate dyslipidemia by targeting the gut microbiome. Further research is needed to determine the efficacy and mechanisms of microbiome-based therapies in managing dyslipidemia [131].
Overall, the development of new therapies targeting leptin and dyslipidemia in obesity is an active area of research. While these therapies are still in the early stages of development, they hold promise for improving outcomes for individuals with obesity-related metabolic conditions.
8. Conclusion
Dyslipidemia is a condition characterized by abnormal levels of lipids, such as cholesterol and triglycerides, in the blood. It is a major risk factor for cardiovascular diseases, including atherosclerosis, heart attack, and stroke. Leptin, a hormone primarily produced by adipose tissue, has been found to play a significant role in dyslipidemia.
One of the key mechanisms through which leptin affects lipid metabolism is by inhibiting the synthesis of fatty acids in adipose tissue. Leptin reduces the activity of an enzyme called fatty acid synthase, which is responsible for converting excess glucose into fatty acids for storage in adipose tissue. By inhibiting this enzyme, leptin helps to reduce the accumulation of fatty acids in adipose tissue and prevent the development of obesity.
Leptin also plays a role in regulating lipid transport in the blood. It has been shown to increase the clearance of triglycerides from the blood by enhancing the uptake and metabolism of triglyceride-rich lipoproteins by the liver. Leptin also promotes the breakdown of triglycerides stored in adipose tissue, releasing fatty acids into the blood to be used as an energy source by other tissues.
Furthermore, leptin has been found to have anti-inflammatory effects, which can have a positive impact on dyslipidemia. Leptin reduces the production of pro-inflammatory cytokines in adipose tissue and liver, which are known to contribute to the development of insulin resistance and atherosclerosis.
Leptin also stimulates the production of anti-inflammatory cytokines, which can help to reduce inflammation and improve lipid metabolism. However, in conditions of obesity; leptin resistance can develop, leading to decreased sensitivity to the effects of leptin. This can result in an imbalance in lipid metabolism and contribute to dyslipidemia.
Acknowledgments
The authors would like to acknowledge Haveri Institute of Medical Sciences, Haveri and St. George’s University School of Medicine, St. George’s, Grenada for their support.
Notes/thanks/other declarations
Nil.
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