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This report is written by MaltSci based on the latest literature and research findings

How do hormones regulate metabolism? ​

Abstract ​

Metabolism is a fundamental biological process involving biochemical reactions that convert food into energy and manage nutrient storage and utilization. Hormones play a crucial role in regulating these metabolic pathways, with insulin, glucagon, thyroid hormones, and adrenal hormones being pivotal in maintaining energy balance and homeostasis. Insulin facilitates glucose uptake, promotes glycogen synthesis, and inhibits gluconeogenesis, while glucagon acts to increase blood glucose levels during fasting by stimulating glycogenolysis and gluconeogenesis. Thyroid hormones are essential for regulating metabolic rate and energy expenditure across various tissues, and adrenal hormones like cortisol manage stress responses and energy mobilization. The interplay between these hormones is complex, and disruptions can lead to metabolic dysfunctions associated with obesity and diabetes. Recent studies also suggest that metabolic hormones influence cognitive functions, linking metabolic disorders with cognitive decline. This review aims to elucidate the mechanisms through which hormones regulate carbohydrate, lipid, and protein metabolism, and discusses the consequences of hormonal dysregulation in relation to metabolic disorders. By synthesizing current research findings, this report provides insights into potential therapeutic strategies for restoring metabolic balance and improving health outcomes for individuals affected by metabolic disorders.

Outline ​

This report will discuss the following questions.

  • 1 Introduction
  • 2 Overview of Metabolism
    • 2.1 Definition and Importance of Metabolism
    • 2.2 Key Metabolic Pathways
  • 3 Hormonal Regulation of Carbohydrate Metabolism
    • 3.1 Role of Insulin
    • 3.2 Role of Glucagon
    • 3.3 Interaction with Other Hormones
  • 4 Hormonal Regulation of Lipid Metabolism
    • 4.1 Role of Insulin and Glucagon in Lipid Metabolism
    • 4.2 Role of Cortisol and Other Adrenal Hormones
  • 5 Hormonal Regulation of Protein Metabolism
    • 5.1 Role of Insulin in Protein Synthesis
    • 5.2 Impact of Glucagon and Other Hormones
  • 6 Consequences of Hormonal Dysregulation
    • 6.1 Metabolic Disorders Overview
    • 6.2 Case Studies: Obesity and Diabetes
  • 7 Summary

1 Introduction ​

Metabolism is a fundamental biological process that encompasses the biochemical reactions responsible for converting food into energy and managing the storage and utilization of nutrients. The intricate balance of these metabolic processes is crucial for maintaining homeostasis, and hormones play a pivotal role in regulating these pathways. Hormones such as insulin, glucagon, thyroid hormones, and adrenal hormones orchestrate a complex network of interactions that not only influence energy expenditure but also impact overall health and disease states. Understanding the mechanisms through which hormones regulate metabolism is of paramount importance, particularly in the context of the rising prevalence of metabolic disorders such as obesity and diabetes, which have become significant public health challenges worldwide.

Recent studies have highlighted the multifaceted roles of hormones in metabolic regulation. For instance, insulin is well-known for its ability to facilitate glucose uptake and regulate lipid and protein metabolism, while glucagon acts to increase blood glucose levels during fasting states [1][2]. Thyroid hormones are critical regulators of energy expenditure and metabolic rate, influencing various tissues including the brain, adipose tissue, liver, and skeletal muscle [3][4]. Additionally, adrenal hormones such as cortisol play essential roles in managing stress responses and energy mobilization [5]. The interplay between these hormones is intricate, as they often interact with one another to fine-tune metabolic responses according to physiological demands.

The significance of hormonal regulation extends beyond mere metabolic control; it also encompasses implications for reproductive health, cognitive function, and the progression of metabolic diseases. Disruptions in hormonal signaling pathways can lead to a cascade of metabolic dysfunctions, which are closely linked to conditions such as obesity and type 2 diabetes [4][6]. Moreover, the impact of hormones on cognitive health and their potential role in linking metabolic disorders with cognitive decline further emphasizes the need for a comprehensive understanding of these regulatory mechanisms [1].

This review aims to elucidate the mechanisms by which various hormones influence metabolic pathways, with a specific focus on carbohydrate, lipid, and protein metabolism. The content is organized as follows: first, we will provide an overview of metabolism, including its definition and key metabolic pathways. Next, we will delve into the hormonal regulation of carbohydrate metabolism, highlighting the roles of insulin and glucagon, as well as their interactions with other hormones. Subsequently, we will explore the hormonal regulation of lipid metabolism, examining the roles of insulin, glucagon, and adrenal hormones such as cortisol. Following this, we will discuss protein metabolism and the contributions of insulin and glucagon. The review will also address the consequences of hormonal dysregulation, particularly in relation to metabolic disorders like obesity and diabetes, supported by case studies that illustrate these concepts. Finally, we will summarize the key findings and discuss potential therapeutic targets for addressing metabolic disorders.

By synthesizing current research findings, this report aims to provide a comprehensive overview of how hormones regulate metabolism, emphasizing the complexity of these interactions and their implications for health and disease. The insights gained from this review may pave the way for novel therapeutic strategies aimed at restoring metabolic balance and improving outcomes for individuals affected by metabolic disorders.

2 Overview of Metabolism ​

2.1 Definition and Importance of Metabolism ​

Metabolism refers to the complex biochemical processes that occur within living organisms to maintain life. It encompasses all the chemical reactions that convert food into energy, enabling growth, reproduction, and maintenance of cellular structures. Metabolism is broadly divided into two categories: catabolism, which breaks down molecules to produce energy, and anabolism, which uses energy to construct components of cells such as proteins and nucleic acids. The regulation of metabolism is crucial for maintaining homeostasis, and hormones play a pivotal role in this regulation.

Hormones are signaling molecules that are secreted by various glands in the endocrine system and have widespread effects on metabolism. They regulate metabolic pathways by influencing the activities of enzymes, modulating the transport of substances across cell membranes, and altering gene expression. For instance, thyroid hormones (THs) are significant modulators of metabolic processes. They control energy balance by acting on multiple tissues, including the brain, adipose tissue, skeletal muscle, liver, and pancreas. THs regulate pathways involved in carbohydrate metabolism, lipid metabolism, and protein synthesis, thereby playing a crucial role in overall energy expenditure and homeostasis (Cicatiello et al., 2018; Sabatino & Vassalle, 2025) [2][7].

Additionally, metabolic hormones such as insulin, glucagon, leptin, and ghrelin are integral to the regulation of energy intake and expenditure. Insulin, secreted by the pancreas, facilitates glucose uptake by cells, promotes glycogen synthesis in the liver, and inhibits gluconeogenesis. Conversely, glucagon acts to increase blood glucose levels by promoting glycogenolysis and gluconeogenesis when energy is needed. Leptin, produced by adipose tissue, informs the brain about energy stores and regulates appetite, while ghrelin, released by the stomach, stimulates hunger (Athar et al., 2024; Ghosh-Swaby et al., 2022) [1][6].

The interplay between these hormones is essential for metabolic homeostasis. For example, disruptions in metabolic hormone signaling can lead to metabolic syndromes such as obesity and diabetes, which are associated with cognitive impairments and other health issues. Research indicates that metabolic hormones not only regulate energy intake but also influence neural plasticity and cognitive functions, highlighting the interconnectedness of metabolism and brain health (Ghosh-Swaby et al., 2022) [1].

Moreover, steroid hormones such as estrogens and androgens also significantly influence metabolic processes. Estrogens, for instance, play a role in controlling energy homeostasis and glucose metabolism, affecting food intake, energy expenditure, and insulin sensitivity. They have been linked to the prevention of lipid accumulation and inflammation, demonstrating their protective effects against metabolic disorders (Mauvais-Jarvis et al., 2013) [8].

In summary, hormones regulate metabolism through a complex network of interactions that involve multiple organs and systems. By modulating the activities of enzymes, influencing nutrient transport, and altering gene expression, hormones ensure that metabolic processes align with the body's energy needs and homeostatic requirements. Understanding these hormonal regulations is vital for developing strategies to address metabolic disorders and improve overall health.

2.2 Key Metabolic Pathways ​

Hormones play a crucial role in regulating metabolism, which encompasses the biochemical processes that convert food into energy and building blocks for growth and repair. The regulation of metabolism by hormones occurs through various mechanisms that influence key metabolic pathways across different tissues.

One of the primary hormones involved in metabolic regulation is insulin, which is secreted by the pancreas in response to elevated blood glucose levels. Insulin facilitates glucose uptake in muscle and adipose tissues, promoting glycogenesis and lipogenesis while inhibiting gluconeogenesis and lipolysis. This anabolic effect is essential for maintaining energy balance and promoting nutrient storage. Conversely, glucagon, another pancreatic hormone, acts to increase blood glucose levels by stimulating glycogenolysis and gluconeogenesis in the liver, particularly during fasting states [1].

Thyroid hormones (THs) also play a pivotal role in metabolic regulation. They are key determinants of cellular metabolism, influencing pathways involved in carbohydrate, lipid, and protein metabolism. Hyperthyroidism leads to a hyper-metabolic state characterized by increased resting energy expenditure, reduced cholesterol levels, and enhanced lipolysis and gluconeogenesis, whereas hypothyroidism results in a hypo-metabolic state with reduced energy expenditure and increased cholesterol levels [7]. THs regulate mitochondrial respiration and biogenesis, which are critical for energy metabolism [9].

In addition to insulin and thyroid hormones, metabolic hormones such as leptin and ghrelin are crucial in the regulation of energy homeostasis and appetite. Leptin, produced by adipose tissue, signals satiety and helps to regulate energy expenditure, while ghrelin, produced by the stomach, stimulates appetite. Disruptions in the signaling of these hormones can lead to metabolic disorders such as obesity and diabetes [1].

The transcriptional coactivator PGC-1α is another important player in metabolic regulation. It responds to hormonal signals that control energy and nutrient homeostasis, inducing gene expression that promotes mitochondrial biogenesis and thermogenesis in brown adipose tissue [10]. This highlights the interplay between hormones and transcriptional regulation in metabolic pathways.

Metabolic pathways are also influenced by sex hormones, which can affect the metabolism of various tissues, including the kidneys and adipose tissue. For instance, estrogens are generally protective against metabolic syndrome, while androgens may exacerbate metabolic issues [11]. Research indicates that visceral adipose tissue (vWAT) may exhibit different metabolic responses in men and women, emphasizing the importance of considering sex differences in metabolic regulation [12].

Overall, the regulation of metabolism by hormones is complex and involves multiple pathways and mechanisms. Hormones not only modulate energy intake and expenditure but also influence the transcriptional and post-translational modifications of metabolic enzymes, thereby integrating signals from various physiological states to maintain metabolic homeostasis. Understanding these hormonal interactions and their effects on metabolic pathways is crucial for developing therapeutic strategies for metabolic disorders.

3 Hormonal Regulation of Carbohydrate Metabolism ​

3.1 Role of Insulin ​

Insulin plays a pivotal role in the regulation of carbohydrate metabolism, primarily through its effects on glucose utilization and production. Secreted by the pancreatic β-cells, insulin facilitates glucose uptake in insulin-sensitive tissues such as muscle and adipose tissue while simultaneously suppressing hepatic glucose production. This action is critical for maintaining normal plasma glucose levels and ensuring adequate energy supply to cells.

Insulin's influence extends beyond glucose metabolism; it also regulates lipid and protein metabolism. In the context of glucose metabolism, insulin stimulates glucose transport into cells, enhances glycogen synthesis in the liver and muscle, and inhibits gluconeogenesis in the liver, thereby reducing the amount of glucose released into the bloodstream [13].

The mechanisms of insulin action are mediated through specific signaling pathways, notably the phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT) pathways. These pathways are crucial for the metabolic effects of insulin, such as promoting glucose uptake and storage, and inhibiting catabolic processes like lipolysis and proteolysis [14].

Insulin also affects the metabolism of fats by promoting lipogenesis and reducing lipolysis, thus increasing the storage of triglycerides in adipose tissue [15]. This anabolic effect is significant in the context of metabolic disorders, where insulin resistance can lead to impaired glucose and lipid metabolism, contributing to conditions such as type 2 diabetes and metabolic syndrome [16].

In summary, insulin is a key hormonal regulator of carbohydrate metabolism, influencing not only glucose homeostasis but also lipid and protein metabolism. Its role in energy storage and utilization highlights its importance in maintaining metabolic health and preventing chronic diseases associated with insulin resistance.

3.2 Role of Glucagon ​

Glucagon is a crucial hormone synthesized and secreted by the pancreatic alpha cells, playing a vital role in the regulation of carbohydrate metabolism, particularly in maintaining blood glucose levels. Its primary function is to counteract the effects of insulin, particularly during periods of hypoglycemia, by stimulating hepatic gluconeogenesis and glycogenolysis. This regulation is essential for maintaining euglycemia, especially in fasting states or during physical stress.

Recent insights into glucagon's role extend beyond mere glucose regulation. It has been recognized as a significant player in amino acid metabolism, particularly during critical illness. Studies have shown that glucagon contributes to hyperglycemia, albeit its role in this process is more complex than previously thought. During critical illness, for instance, increased glucagon levels are associated with hypoaminoacidemia due to its stimulation of hepatic amino acid breakdown, which occurs without affecting muscle wasting. This feedback loop between glucagon and circulating amino acids highlights its intricate role in metabolic homeostasis[17].

Moreover, glucagon's metabolic functions are not limited to glucose and amino acids. It also plays a role in lipid metabolism and has been implicated in the regulation of energy balance. The interaction of glucagon with other hormones, such as insulin, reflects a delicate balance necessary for metabolic health. This interplay is further complicated in conditions like type 2 diabetes, where glucagon's secretion may become dysregulated, contributing to the disease's pathophysiology[18].

Glucagon's actions are mediated through its receptors, and recent advancements in pharmacological approaches, such as glucagon receptor antagonists and agonists, have shed light on its potential therapeutic applications. For instance, glucagon receptor agonism has shown promise in treating metabolic disorders, including obesity and fatty liver diseases, by enhancing lipid oxidation and energy expenditure[19].

In summary, glucagon serves as a pivotal hormone in the regulation of carbohydrate metabolism, influencing not only glucose homeostasis but also amino acid and lipid metabolism. Its multifaceted role underscores the complexity of hormonal regulation in metabolic processes and highlights the potential for glucagon-targeted therapies in managing metabolic diseases[20][21][22].

3.3 Interaction with Other Hormones ​

Hormones play a crucial role in regulating metabolism, particularly carbohydrate metabolism, through complex interactions with other hormones and signaling pathways. The regulation of carbohydrate metabolism is essential for maintaining cellular energy balance and supporting the biosynthesis of new cellular components. Hormonal signaling is pivotal in mediating intertissue communication, thereby maintaining organismal homeostasis.

One of the key hormones involved in carbohydrate metabolism is insulin, which works in concert with growth hormone (GH) and insulin-like growth factor 1 (IGF-1). The interaction between IGF-1 and GH is particularly significant, as they modulate insulin's control over carbohydrate metabolism. A study indicated that blocking the effect of GH in the presence of low serum IGF-1 concentrations enhances insulin sensitivity, suggesting that the balance between these hormones is critical for optimal metabolic function (Clemmons 2004) [23].

In addition to insulin, GH and IGF-1, thyroid hormones also play a vital role in regulating various metabolic processes, including carbohydrate metabolism. Thyroid hormones influence protein synthesis and breakdown, cardiovascular function, and energy metabolism. The discovery of new polymorphs of synthetic L-thyroxine (T4) highlights the importance of thyroid hormone activity, as polymorphism can affect hormone solubility and activity, thus impacting metabolic regulation (Mondal and Mugesh 2015) [24].

Moreover, the adaptation of metabolism to dietary changes involves hormonal regulation at the cellular level. When there is a fluctuation in carbohydrate or fat intake, hormonal signals alter metabolic pathways by modifying the flux of intermediates into cells. This process influences the concentration of hormones and other signaling molecules, which in turn changes the expression rate of genes coding for key regulatory proteins or enzymes in metabolic pathways. Transcription factors play a significant role in these adaptations, integrating the effects of hormones and nutrients to regulate gene expression crucial for energy metabolism (Leahy et al. 1999) [25].

In summary, hormonal regulation of carbohydrate metabolism is a multifaceted process involving insulin, GH, IGF-1, and thyroid hormones. These hormones interact with one another and influence metabolic pathways through gene expression and transcription factor activity, ensuring that energy metabolism is finely tuned to meet the physiological needs of the organism. Misregulation of these hormonal interactions can lead to metabolic disorders, underscoring the importance of understanding these complex regulatory mechanisms.

4 Hormonal Regulation of Lipid Metabolism ​

4.1 Role of Insulin and Glucagon in Lipid Metabolism ​

Hormones play a critical role in regulating metabolism, particularly in the context of lipid metabolism, with insulin and glucagon being two of the most influential hormones in this process.

Insulin, a polypeptide hormone secreted by the β cells in the islets of Langerhans of the pancreas, primarily acts through anabolic pathways. It regulates blood glucose levels by promoting glucose uptake in various tissues, including the liver, muscles, and adipose tissue, leading to increased storage of glucose as glycogen and fat as triglycerides. Insulin inhibits lipolysis in adipose tissue by suppressing lipase activity, thereby reducing the flux of free fatty acids into the bloodstream. It also decreases very-low-density lipoprotein (VLDL) production in the liver and promotes the clearance of low-density lipoprotein (LDL) by enhancing the activity of the LDL receptor, which is critical for maintaining lipid homeostasis [26].

On the other hand, glucagon, also produced by the pancreatic islets, has catabolic effects that counteract those of insulin. Glucagon increases blood glucose levels primarily by stimulating gluconeogenesis and glycogenolysis in the liver. Furthermore, glucagon promotes lipolysis, leading to the release of free fatty acids into the circulation for energy metabolism. It is important to note that glucagon’s role extends beyond glucose regulation; it also influences lipid metabolism by promoting fat oxidation and decreasing triglyceride synthesis in the liver [22].

The interplay between insulin and glucagon is vital for maintaining metabolic homeostasis. For instance, during fasting, glucagon levels rise to facilitate the mobilization of energy stores, while insulin levels decrease. Conversely, postprandial (after eating) states see increased insulin secretion to facilitate nutrient storage, with glucagon levels dropping [27]. This regulatory mechanism is crucial for preventing metabolic disorders, as imbalances can lead to conditions such as insulin resistance and type 2 diabetes [28].

Moreover, the hormonal regulation of lipid metabolism is influenced by various factors, including dietary fatty acids. Polyunsaturated fatty acids (PUFAs) have been shown to increase insulin sensitivity and promote insulin secretion, whereas saturated and trans fatty acids can lead to insulin resistance [29]. The interaction between dietary fats and hormonal signaling pathways further underscores the complexity of metabolic regulation [27].

In summary, insulin and glucagon play complementary roles in lipid metabolism, with insulin primarily facilitating energy storage and glucagon promoting energy mobilization. Their balanced interaction is essential for maintaining metabolic health, and disruptions in this balance can contribute to metabolic diseases.

4.2 Role of Cortisol and Other Adrenal Hormones ​

Hormones play a crucial role in regulating lipid metabolism through various mechanisms, particularly through the actions of cortisol and other adrenal hormones. Cortisol, a steroid hormone produced in the adrenal cortex, is integral to energy metabolism, stress responses, and immune function. Its levels are regulated by the hypothalamic-pituitary-adrenal (HPA) axis, which operates on a negative feedback loop, adhering to a circadian rhythm. Disruptions in this axis can lead to significant health issues, including psychiatric, cardiovascular, and metabolic disorders, which are often associated with altered cortisol secretion rates[30].

Cortisol influences lipid metabolism by facilitating lipid accumulation through the expression of lipoprotein lipase (LPL), a key enzyme in fat storage. It acts via glucocorticoid receptors, which are more densely present in visceral adipose tissue compared to subcutaneous tissue. This receptor-mediated action likely involves the transcription of specific genes that regulate lipid storage and mobilization[31]. In contrast, growth hormone (GH) has the opposite effect; it promotes lipid mobilization and inhibits LPL, thereby stimulating lipolysis, the breakdown of fats for energy[31].

The interplay between cortisol and other hormones such as insulin, glucagon, and catecholamines further illustrates the complexity of hormonal regulation in lipid metabolism. Insulin promotes lipogenesis, while glucagon stimulates lipolysis, thus modulating fatty acid concentrations in plasma and tissues[29]. Additionally, polyunsaturated fatty acids (PUFAs) have been shown to enhance insulin sensitivity and alter the levels of various hormones, indicating a bidirectional relationship between fatty acids and hormonal regulation[27].

Furthermore, thyroid hormones significantly impact lipid metabolism by regulating hepatic fatty acid and cholesterol synthesis. Hypothyroidism is associated with increased triglyceride and cholesterol levels, which underscores the importance of thyroid hormones in maintaining lipid homeostasis[32]. They mediate these effects through various mechanisms, including the modulation of lipogenesis and β-oxidation pathways in the liver[32].

The regulation of lipid metabolism by hormones is not only confined to energy balance but also involves the intricate interactions between different hormonal pathways. For instance, adrenal hormones like catecholamines released from the adrenal medulla can influence lipid metabolism through their effects on adipose tissue and energy expenditure[33].

In summary, hormonal regulation of lipid metabolism is a multifaceted process that involves various hormones, including cortisol, GH, insulin, glucagon, and thyroid hormones. Each of these hormones plays a distinct role in either promoting or inhibiting lipid storage and mobilization, highlighting the intricate balance required for maintaining metabolic health. Disruptions in these hormonal pathways can lead to metabolic disorders, emphasizing the importance of understanding these regulatory mechanisms for potential therapeutic interventions in conditions such as obesity and cardiovascular disease.

5 Hormonal Regulation of Protein Metabolism ​

5.1 Role of Insulin in Protein Synthesis ​

Hormones play a critical role in regulating metabolism, particularly in the context of protein metabolism. Among these hormones, insulin is a key anabolic hormone that significantly influences protein synthesis and degradation processes. Insulin regulates protein metabolism through several mechanisms, impacting both the synthesis of proteins and the breakdown of proteins in various tissues.

Insulin's primary function is to facilitate the uptake of glucose and amino acids into cells, which are essential for protein synthesis. It stimulates glucose transport into cells and suppresses hepatic glucose production, thus maintaining energy availability for anabolic processes [14]. Insulin also influences the growth and differentiation of cells, enhances protein synthesis, and inhibits catabolic processes such as glycolysis, lipolysis, and proteolysis [14].

One of the fundamental ways insulin exerts its effects on protein metabolism is through the regulation of gene expression. Insulin has been shown to modulate the transcription of various genes associated with protein synthesis and degradation. For instance, insulin inhibits the transcription of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK), leading to a decrease in its mRNA levels and consequently affecting protein synthesis [34]. Furthermore, insulin activates intracellular signaling pathways, such as the phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) pathways, which are crucial for the regulation of translation initiation and the synthesis of proteins [35].

The interaction between insulin and amino acids is also significant in the context of protein metabolism. Amino acids act as signaling molecules that can enhance the anabolic effects of insulin. When insulin levels are adequate, it promotes the uptake of amino acids into cells, where they can be utilized for protein synthesis. Insulin not only inhibits protein degradation but can also stimulate protein synthesis, creating a favorable environment for muscle growth and repair [36].

Moreover, the regulation of protein metabolism by insulin is closely tied to its role in maintaining proteostasis, which is essential for normal cellular function. Insulin signaling is involved in the balance of protein synthesis and degradation, ensuring that the cellular proteome remains stable and functional [37]. In conditions of insulin resistance, this balance is disrupted, leading to increased protein breakdown and decreased synthesis, which can contribute to muscle wasting and other metabolic disorders [15].

In summary, insulin regulates protein metabolism through multiple mechanisms, including the modulation of gene expression, activation of key signaling pathways, and interaction with amino acids. These processes collectively determine the rates of protein synthesis and degradation, highlighting the central role of insulin in anabolic metabolism and overall metabolic health.

5.2 Impact of Glucagon and Other Hormones ​

Hormones play a crucial role in regulating metabolism, particularly protein metabolism, by influencing various biochemical pathways that govern protein synthesis and breakdown. Among these hormones, glucagon, insulin, growth hormone, and others significantly impact protein kinetics in the human body.

Glucagon, primarily known for its role in glucose metabolism, also exerts a catabolic effect on protein metabolism. It is released from the pancreatic alpha cells and acts to increase blood glucose levels by stimulating hepatic gluconeogenesis and glycogenolysis. In addition to these functions, glucagon influences amino acid metabolism. Studies indicate that during conditions of amino acid load, glucagon can inhibit protein synthesis by decreasing the availability of amino acids, thus promoting a catabolic state. For instance, in a controlled study, glucagon infusion led to a decrease in nonoxidative leucine flux, which reflects protein synthesis, while enhancing leucine oxidation, indicative of increased proteolysis (Charlton et al. 1996) [38].

The hormonal regulation of protein metabolism can be categorized based on their effects on protein balance, which is defined as the difference between protein synthesis and breakdown. Anabolic hormones, such as insulin and growth hormone, promote protein synthesis and muscle growth, while catabolic hormones like glucagon and glucocorticoids tend to promote protein breakdown. Insulin, for example, stimulates protein synthesis by facilitating amino acid uptake into cells and activating signaling pathways that enhance translation and inhibit proteolysis. In contrast, glucagon's action during amino acid infusion appears to be predominantly catabolic, as it prevents the expected increase in amino acids and protein synthesis, demonstrating its pivotal role in amino acid disposal (Thiessen et al. 2018) [17].

Moreover, the interplay between glucagon and other hormones is critical in metabolic regulation. Insulin and glucagon are often viewed as antagonistic; however, their interactions are more complex. For instance, during postprandial states, protein ingestion can lead to simultaneous increases in both insulin and glucagon levels, which work together to maintain euglycemia while regulating amino acid and nitrogen metabolism (Ang et al. 2019) [39]. This cooperative action highlights the importance of considering the broader hormonal context rather than isolating individual hormones when examining their metabolic effects.

In the context of critical illness, glucagon's role becomes even more pronounced. Increased glucagon availability has been associated with hyperaminoacidemia and muscle wasting, as it stimulates hepatic amino acid breakdown without significantly affecting muscle protein degradation (Thiessen et al. 2018) [17]. This suggests that elevated glucagon levels during critical illness may contribute to the observed hypoaminoacidemia, complicating the management of protein intake in such patients.

In conclusion, hormones such as glucagon play multifaceted roles in regulating protein metabolism, influencing both catabolic and anabolic processes. The delicate balance between these hormonal signals is essential for maintaining metabolic homeostasis, particularly in response to dietary changes and physiological stressors. Understanding these interactions can provide insights into potential therapeutic strategies for metabolic disorders characterized by hormonal imbalances.

6 Consequences of Hormonal Dysregulation ​

6.1 Metabolic Disorders Overview ​

Hormones play a critical role in regulating metabolism by influencing various physiological processes, including energy intake, nutrient utilization, and overall metabolic homeostasis. The dysregulation of hormonal signaling can lead to significant metabolic disorders, which have been increasingly recognized as important factors in various health conditions, including obesity, diabetes, and cardiovascular diseases.

Thyroid hormones, for instance, are pivotal in the modulation of energy balance and metabolism. Dysregulation of the thyroid axis can result in marked alterations in energy expenditure and food intake. The potential of thyroid hormones in treating obesity has been acknowledged for decades; however, their therapeutic application has been limited due to side effects. Recent studies have elucidated the mechanisms of action of thyroid hormones, revealing that they act on specific energy sensors, such as AMP-activated protein kinase and mechanistic target of rapamycin, in hypothalamic neurons. These interactions mediate effects on energy expenditure, glucose and lipid metabolism, and cardiovascular function, highlighting the relevance of understanding these molecular mechanisms for treating obesity and metabolic syndrome (Martínez-Sánchez et al., 2014) [40].

Furthermore, metabolic hormones are not only crucial for regulating energy intake but also for modulating cognitive functions. Evidence suggests that metabolic hormones, including ghrelin, leptin, and insulin, influence neural plasticity and cognition. Disruptions in the signaling of these hormones can link metabolic syndromes like obesity and diabetes to cognitive impairments. For instance, altered metabolic homeostasis in obesity has been associated with an increased severity of age-related cognitive decline and neurodegenerative diseases. Therapeutic interventions that restore metabolic hormone levels, such as caloric restriction and antidiabetic therapies, have shown promise in enhancing cognitive function, underscoring the potential of targeting metabolic hormone pathways in the treatment of cognitive decline (Ghosh-Swaby et al., 2022) [1].

The interplay between metabolic dysregulation and cancer progression also illustrates the consequences of hormonal dysregulation. In hormone-dependent cancers such as prostate and breast cancer, metabolic dysregulation is a significant driver of tumor development. The role of nuclear hormone receptors, such as estrogen and androgen receptors, is crucial in regulating lipid metabolism, which remains dysregulated as cancer progresses. This understanding opens avenues for drug repurposing and the development of new therapeutic strategies targeting metabolic pathways in cancer treatment (Poulose et al., 2018) [41].

Moreover, in the context of HIV infection, metabolic disturbances associated with both the disease and antiretroviral therapy can lead to insulin and glucose dysregulation, lipid abnormalities, and other metabolic disorders. These complications have serious implications for long-term health outcomes, including increased cardiovascular risk (Martin & Emery, 2009) [42].

In summary, hormonal regulation of metabolism is multifaceted, involving complex interactions between various metabolic hormones and their receptors. Dysregulation of these hormonal pathways can lead to a range of metabolic disorders, with significant implications for health and disease management. Understanding these relationships is crucial for developing effective therapeutic strategies aimed at mitigating the impact of metabolic disorders on overall health.

6.2 Case Studies: Obesity and Diabetes ​

Hormones play a crucial role in regulating metabolism, influencing various physiological processes such as energy intake, nutrient utilization, and overall metabolic homeostasis. Dysregulation of hormonal signaling can lead to significant metabolic disorders, including obesity and diabetes.

Metabolic hormones such as ghrelin, leptin, and insulin are pivotal in modulating neural plasticity and cognition, thereby impacting energy balance and metabolic homeostasis. For instance, disruptions in the signaling of these hormones are linked to metabolic syndromes like obesity and diabetes, which in turn correlate with cognitive impairments. Research indicates that altered metabolic homeostasis in obesity significantly exacerbates age-related cognitive decline and neurodegenerative diseases, suggesting that metabolic hormone pathways could be promising targets for therapeutic interventions aimed at cognitive decline (Ghosh-Swaby et al., 2022) [1].

Obesity, characterized by an imbalance in energy intake and expenditure, is a significant risk factor for the development of type 2 diabetes and other cardiometabolic diseases. Insulin resistance, often resulting from dysregulated hormonal and metabolic signaling, is a hallmark of obesity. Insulin, an anabolic hormone, regulates lipid, carbohydrate, and protein metabolism in key tissues, including adipose tissue, liver, and skeletal muscle. In the context of obesity, the impaired action of insulin on its target organs leads to metabolic dysfunction and increased insulin resistance, primarily driven by the dysfunctional state of adipose tissue (Sjöstrand & Eriksson, 2009) [43].

Sex differences also play a significant role in the regulation of metabolism. Evidence shows that males are more prone to develop obesity and insulin resistance compared to females, partially due to differences in fat distribution and hormonal influences. Estrogens, for instance, contribute to a protective effect against metabolic disorders in females by regulating the distribution and function of adipose tissue. Hypothalamic estrogen signaling has been shown to modulate white adipose tissue (WAT) distribution and thermogenic activity in brown adipose tissue (BAT), indicating a complex interplay between sex hormones and metabolic regulation (Torres Irizarry et al., 2022) [44].

The pathophysiology of obesity and its consequences on metabolic health highlight the critical role of adipocytes in endocrine regulation. Adipocytes secrete various hormones and mediators that influence not only local tissue microenvironments but also systemic metabolic functions. The dysfunction of these cells can lead to inflammation and further exacerbate cardiovascular risks associated with obesity (Giroud et al., 2022) [45].

Furthermore, neuroinflammation resulting from obesity is linked to disruptions in the hypothalamic-pituitary-gonadal axis, affecting reproductive function and contributing to the cycle of metabolic dysregulation. Elevated levels of insulin, lipids, and leptin associated with obesity are believed to disrupt the normal function of gonadotropin-releasing hormone (GnRH) neurons, which are crucial for reproductive regulation (Lainez & Coss, 2019) [46].

In summary, hormonal regulation of metabolism is a complex interplay involving various hormones that modulate energy balance and metabolic processes. Dysregulation of these hormonal pathways can lead to obesity and diabetes, underscoring the importance of understanding these mechanisms for developing targeted therapeutic strategies to combat metabolic diseases.

7 Conclusion ​

The intricate regulation of metabolism by hormones is essential for maintaining homeostasis and overall health. This review highlights key findings regarding the roles of various hormones, including insulin, glucagon, thyroid hormones, and adrenal hormones, in metabolic pathways. Insulin is a central player in carbohydrate and lipid metabolism, promoting energy storage and inhibiting catabolic processes. Glucagon, in contrast, stimulates gluconeogenesis and lipolysis, counterbalancing insulin's effects. Thyroid hormones regulate metabolic rate and energy expenditure, while adrenal hormones like cortisol manage stress responses and influence fat distribution. Disruptions in these hormonal interactions can lead to significant metabolic disorders, including obesity and diabetes, emphasizing the need for a deeper understanding of these pathways. Future research should focus on elucidating the molecular mechanisms of hormonal regulation and exploring potential therapeutic targets to restore metabolic balance, particularly in the context of rising metabolic disorders globally. Furthermore, addressing the interplay between hormonal dysregulation and cognitive health may open new avenues for interventions aimed at improving both metabolic and neurological outcomes.

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