Impact Of Obesity On The Development Of Endocrine Disease Essay
Impact Of Obesity On The Development Of Endocrine Disease Essay
Previously undiagnosed endocrine disease is almost never the cause of obesity. Hypothyroidism is rare as a cause, and thyroxine replacement seldom produces dramatic weight loss. Hyperphagia and weight gain are sometimes seen in thyrotoxicosis. Cushing’s syndrome is a rare cause of obesity, but it is important to consider this possibility when assessing obese patients. Adults with growth hormone deficiency exhibit increased body fat and reduced lean body mass, which can be corrected by growth hormone replacement. Impact Of Obesity On The Development Of Endocrine Disease Essay. Obesity is often a feature of polycystic ovary syndrome, but not a consequence of polycystic ovaries
Hypothalamic obesity
It is exceedingly rare for previously unrecognized hypothalamic disease to present as obesity. Tumours in the hypothalamic region (notably craniopharyngiomas and pituitary macroadenomas with suprasellar extension) often damage the ventromedial hypothalamic regions that regulate energy intake and expenditure. Similar lesions may also occur following trauma or surgery. Such patients often exhibit marked hyperphagia but also have autonomic imbalance leading to hyperinsulinaemia, which can exacerbate weight gain by promoting fat deposition
Physical activity may be reduced as a result of somnolence or associated visual loss. Endocrine disturbances (particularly growth hormone deficiency and hypogonadism) may contribute to an unfavourable body fat distribution, increasing metabolic risk in this group
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Drugs
Many drugs (notably centrally acting drugs, such as anticonvulsants, and neuroleptic agents) promote weight gain. The mechanisms depend on the agent concerned and are not well understood, but may involve both central effects on appetite (thought to be the case with neuroleptics) and peripheral metabolic effects (with oral hypoglycaemic drugs and protease inhibitors) Patients taking such drugs must be informed of this side-effect and of dietary measures to prevent it. In some cases, alternatives are available that do not promote weight gain.Impact Of Obesity On The Development Of Endocrine Disease Essay.
Eating disorders and psychiatric causesobesity is a common underlying problem with the psychiatric disease bulimia nervosa through episodic binge-eating, which may be accompanied by self-induced vomiting. Voluntary overeating is sometimes a response to psychological stress, for example to previous sexual abuse in young women (Stunkard and Wadden, 2014) Although many obese patients say they feel depressed (mainly about their weight) and they eat to excess when they feel this, this symptom is not the same as true endogenous depression and these problems are not helped by antidepressant drugs (Stunkard and Wadden, 2014)
Of the 1119 new patients admitted to the ICU between November 2012 and August 2013, 230 had recorded BMI data. Of these, the majority of patients were male (58%), either overweight or obese (75.2%) with a mean age of 56.8 years. Out of the patients with a normal BMI, 32.7% were in the neurosurgery specialty, compared to only 11.1% of obese patients. Whereas, out of the patients who were classified as underweight, 37.5% were in the general surgical/gastro/liver/renal specialty compared to only 15.7% of overweight patients. With 75% of the sample overweight or obese Australian ICU patients may have higher BMI than those of the general Australian population. Therefore there may be hidden ICU costs attributable to the presence and management of this cohort. No medical specialty was associated with higher BMI than another within this ICU population sample, however it may be that larger patient numbers may have detected differences (Australia New ZealandIntensive Care Society, 2013)
Impact of increased body mass index on sepsis mortality
At least 25 % of adults admitted to intensive care units (ICU) in the United States have overweight, obese, or morbidly obese body mass indices (BMIs), while bacterial sepsis is commonly the cause for these admissions. Impact Of Obesity On The Development Of Endocrine Disease Essay. Although an obese BMI reduces overall life expectancy, it is unclear whether it also impacts the acute outcome of ICU patients in general, or with sepsis specifically (Angus et al, 2001) While identifying such an association has important prognostic and therapeutic implications, this is difficult because an obese BMI is one of several variables potentially influencing ICU outcomes. Studies addressing this question provide conflicting and unclear results
A recent analysis of seven studies of septic patients found an obese BMI increased, decreased, or had no effect on survival. However, two of the studies included non-ICU and ICU patients for whom the overall risk of death would have differed. Furthermore, one study included children and adults, and another study did not account for other baseline variables. Based on the adverse effects of an obese BMI on long term health, an increased BMI would also worsen short-term outcomes in adult patients with sepsis requiring ICU care. To examine this question, a meta-analysis of studies was performed in adult patients admitted to the ICU (participants) and treated for sepsis, severe sepsis, or septic shock (interventions/exposures)
Sepsis and severe sepsis are the most common cause of death among critically ill patients admitted in medical intensive care units. As per the Centers for Disease Control and Prevention National Center for Health statistics report, septicemia was the 11th leading cause of death in the United States in 2010. Between 2003 and 2007, the number of patients hospitalized for severe sepsis increased by 71%, at an annual rate of 17.8% per year. In addition to high mortality and morbidity, severe sepsis is associated with increased health care expenditures. In 2007, the health care costs for patients admitted for severe sepsis exceeded $24 billion, an increase of 57% since 2003
Obesity is one of the major public health problems. Current estimates suggest that 69% of adults in United States are either overweight or obese with approximately 35% obese. Furthermore, overweight and obesity are major contributors to chronic diseases. Obesity has been shown to be associated with an increased all cause mortality, myocardial infarction, diabetes mellitus, and hypertension (Prescott et al., 2014). The high prevalence of obesity in the general population has led to a higher number of obese patients being hospitalized in ICUs. Impact Of Obesity On The Development Of Endocrine Disease Essay.
Hormones are chemical messengers that regulate processes in our body. They are one factor in causing obesity. The hormones leptin and insulin, sex hormones and growth hormone influence our appetite, metabolism (the rate at which our body burns kilojoules for energy), and body fat distribution. People who are obese have levels of these hormones that encourage abnormal metabolism and the accumulation of body fat.
A system of glands, known as the endocrine system, secretes hormones into our bloodstream. The endocrine system works with the nervous system and the immune system to help our body cope with different events and stresses. Excesses or deficits of hormones can lead to obesity and, on the other hand, obesity can lead to changes in hormones.
Obesity and leptin
The hormone leptin is produced by fat cells and is secreted into our bloodstream. Leptin reduces a person’s appetite by acting on specific centres of their brain to reduce their urge to eat. It also seems to control how the body manages its store of body fat.
Because leptin is produced by fat, leptin levels tend to be higher in people who are obese than in people of normal weight. However, despite having higher levels of this appetite-reducing hormone, people who are obese aren’t as sensitive to the effects of leptin and, as a result, tend not to feel full during and after a meal. Ongoing research is looking at why leptin messages aren’t getting through to the brain in people who are obese.
Obesity and insulin
Insulin, a hormone produced by the pancreas, is important for the regulation of carbohydrates and the metabolism of fat. Insulin stimulates glucose (sugar) uptake from the blood in tissues such as muscles, the liver and fat. This is an important process to make sure that energy is available for everyday functioning and to maintain normal levels of circulating glucose.
In a person who is obese, insulin signals are sometimes lost and tissues are no longer able to control glucose levels. This can lead to the development of type II diabetes and metabolic syndrome.
Obesity and sex hormones
Body fat distribution plays an important role in the development of obesity-related conditions such as heart disease, stroke and some forms of arthritis. Fat around our abdomen is a higher risk factor for disease than fat stored on our bottom, hips and thighs. It seems that oestrogens and androgens help to decide body fat distribution. Oestrogens are sex hormones made by the ovaries in pre-menopausal women. They are responsible for prompting ovulation every menstrual cycle.
Men and postmenopausal women do not produce much oestrogen in their testes (testicles) or ovaries. Instead, most of their oestrogen is produced in their body fat, although at much lower amounts than what is produced in pre-menopausal ovaries. In younger men, androgens are produced at high levels in the testes. As a man gets older, these levels gradually decrease.
The changes with age in the sex hormone levels of both men and women are associated with changes in body fat distribution. While women of childbearing age tend to store fat in their lower body (‘pear-shaped’), older men and postmenopausal women tend to increase storage of fat around their abdomen (‘apple-shaped’). Postmenopausal women who are taking oestrogen supplements don’t accumulate fat around their abdomen. Animal studies have also shown that a lack of oestrogen leads to excessive weight gain.
Obesity and growth hormone
The pituitary gland in our brain produces growth hormone, which influences a person’s height and helps build bone and muscle. Growth hormone also affects metabolism (the rate at which we burn kilojoules for energy). Researchers have found that growth hormone levels in people who are obese are lower than in people of normal weight.
Inflammatory factors and obesity
Obesity is also associated with low-grade chronic inflammation within the fat tissue. Excessive fat storage leads to stress reactions within fat cells, which in turn lead to the release of pro-inflammatory factors from the fat cells themselves and immune cells within the adipose (fat) tissue.
Obesity hormones as a risk factor for disease
Obesity is associated with an increased risk of a number of diseases, including cardiovascular disease, stroke and several types of cancer, and with decreased longevity (shorter life span) and lower quality of life. For example, the increased production of oestrogens in the fat of older women who are obese is associated with an increase in breast cancer risk, indicating that the source of oestrogen production is important. Impact Of Obesity On The Development Of Endocrine Disease Essay.
Behaviour and obesity hormones
People who are obese have hormone levels that encourage the accumulation of body fat. It seems that behaviours such as overeating and lack of regular exercise, over time, ‘reset’ the processes that regulate appetite and body fat distribution to make the person physiologically more likely to gain weight. The body is always trying to maintain balance, so it resists any short-term disruptions such as crash dieting.
Various studies have shown that a person’s blood leptin level drops after a low-kilojoule diet. Lower leptin levels may increase a person’s appetite and slow down their metabolism. This may help to explain why crash dieters usually regain their lost weight. It is possible that leptin therapy may one day help dieters to maintain their weight loss in the long term, but more research is needed before this becomes a reality.
There is evidence to suggest that long-term behaviour changes, such as healthy eating and regular exercise, can re-train the body to shed excess body fat and keep it off.Impact Of Obesity On The Development Of Endocrine Disease Essay. Studies have also shown that weight loss as a result of healthy diet and exercise or bariatric surgery leads to improved insulin resistance, decreased inflammation and beneficial modulation of obesity hormones. Weight loss is also associated with a decreased risk of developing heart disease, stroke, type II diabetes and some cancers.
Obesity can be associated with several endocrine alterations arising as a result of changes in the hypothalamic-pituitary hormones axes. These include hypothyroidism, Cushing’s disease, hypogonadism and growth hormone deficiency. Besides its role in energy storage, adipose tissue has many other important functions that can be mediated through hormones or substances synthesized and released by adipocytes which include leptin and adiponectin. Further, obesity is also a common feature of polycystic ovarian syndrome with hyperinsulinemia being the primary etiological factor. Here, we provide and an overview of certain endocrine syndromes which are known to result in obesity and discuss the endocrine role of adipose tissue in conjunction to its association with hypothalamic-pituitary-endocrine axes. For complete coverage of this and related areas of Endocrinology, please visit our free online textbook, WWW.ENDOTEXT.ORG.
INTRODUCTION
This chapter will discuss the endocrine role of adipose tissue and how alterations in each of the hypothalamic-pituitary-endocrine axes can occur in association with obesity. Of particular relevance is the possible bidirectionality of the relationships between endocrine changes and obesity: whether they are secondary to obesity or, in some cases, be a contributive factor to the development and/or perpetuation of obesity.
The endocrine axes of the human body are dynamic systems; they frequently show changes in response to stress, disease or other pathological states. For example, during acute and chronic illnesses, and low calorie or starvation states, levels of thyroid, gonadal, and growth hormone are altered, returning to normal as the subject recovers. These hormonal changes are, therefore, thought to be secondary to the disease state and their recovery is reflective of a homeostatic mechanism. Often these “adaptive” changes in hormonal dynamics may not necessarily be appropriate. Likewise, therapeutic measures aimed at restoring “normal” serum level of perturbed hormones offered in hopes of hastening recovery and improve patient outcomes have generally not been shown to be beneficial.
The weight gain that leads to obesity is the consequence of a positive energy balance, which can result from an increased energy intake, decreased energy expenditure, or both. This misalignment may be thought of as a failure of the body’s homeostatic mechanisms to match energy intake with expenditure. Different phenotypes of obesity may have variable health implications. Abdominal obesity is considered to be a more hazardous condition than gluteofemoral, or gynecoid, obesity. In those with abdominal obesity, accumulation of intraperitoneal fat in the omentum and around viscera carries greater health risk than subcutaneous abdominal obesity. Therefore, when discussing complications of and metabolic abnormalities associated with obesity, different phenotypes of obesity exist and carry different degrees of risk, in particular cardiometabolic risk.
Our understanding of the physiology of adipose tissue has greatly advanced in the last decade and extensive research has been dedicated to the study of the interactions between the adipose tissue and other bodily systems, in particular the central nervous system. New hormones have been discovered with potentially important roles in energy balance and food intake. Impact Of Obesity On The Development Of Endocrine Disease Essay.The roles of many of these newly discovered hormones have not been fully elucidated in humans, but the future holds promise in not only improving our knowledge of the pathophysiology of obesity but also in developing novel therapeutic approaches to complement our currently, rather limited, pharmacological arsenal.
Adipose Tissue
Besides its role in energy storage, adipose tissue has many other important functions that can be mediated through hormones or substances synthesized and released by adipocytes. These substances, “adipocytokines,” are capable of acting on distant targets in an endocrine fashion or locally in paracrine and autocrine fashions. In the following paragraphs, we shall discuss a few of the important adipocytokines secreted from “white” fat. A discussion of “brown” fat, which helps regulate thermogenesis, is beyond the scope of this chapter (1).
Leptin
The hormone leptin (from the Greek word ”leptos” meaning ”thin”) is a 167-amino acid peptide hormone encoded by the ob (obesity) gene and secreted by white adipocytes. Its discovery in 1994, has greatly improved our understanding of how the adipose tissue “communicates” with other systems in the body, in particular with the central nervous system (CNS) (2-4). Following release into the circulation, leptin crosses the blood–brain barrier and binds to presynaptic GABAergic neurons to of the hypothalamus of the central nervous system (CNS) to control appetite and energy expenditure (5). One of leptin’s more important roles is thought to be as a signal of inadequate food intake or starvation. For example, leptin levels decline during fasting, low-calorie dieting, or uncontrolled type 1 diabetes. In these situations, the reduced leptin levels stimulate hunger while decreasing energy expenditure and engendering other physiologic adaptations that restore fat stores to baseline (6, 7).
On the other hand, serum concentrations of leptin increase in proportion to increasing adiposity. As a regulatory signal in a homeostatic system, higher circulating levels of leptin should result in decreased energy intake and elevated energy expenditure, but this is not the case when individuals become overweight or obese, suggesting a state of leptin resistance. Obesity is associated with decreasing levels of circulating soluble leptin receptors (SLR) (8). These receptors are proteins that circulate in the blood and contribute directly to leptin function (8, 9). This state of high leptin levels and low SLR may explain in part why obese individuals are resistant to leptin (10). Impact Of Obesity On The Development Of Endocrine Disease Essay. Decreased transport across the blood-brain barrier (9, 11) and also a decreased ability of leptin to activate hypothalamic signaling in diet-induced obesity (12-15) may be crucial mediators in the pathogenesis of leptin resistance that leads to failure to adequately compensate for the positive energy balance leading to unwanted weight gain and obesity. This postulated leptin resistance is a major target in the search for a better understanding of obesity and the development of pharmacological tools to treat this chronic disease.
Leptin not only links fat tissue with the CNS, but also to other tissues in the body. Leptin receptors are present in peripheral organs, such as the liver, skeletal muscles, pancreatic beta cells, and even adipose cells, indicating endocrine, autocrine, and paracrine roles of leptin in energy regulation. Leptin signaling in these organs is thought to mediate important metabolic effects. Leptin has been implicated in glucose and lipid metabolism as an insulin-sensitizer (16, 17). It has been shown to decrease glucagon synthesis and secretion, decrease hepatic glucose production and increase insulin hepatic extraction, decrease lipogenesis in the adipose tissue and increase lipolysis among multiple other beneficial effects on insulin and lipids metabolism (18).
Leptin plays a significant permissive role in the physiological regulation of several neuroendocrine axes, including the hypothalamic-pituitary-gonadal, -thyroid, -growth hormone, and -adrenal axes (19, 20). Leptin regulates reproductive function by altering the sensitivity of the pituitary gland to GnRH and acting at the ovary to alter follicular and luteal steroidogenesis, proliferation, and apoptosis (20). Thus leptin serves as a putative signal that links metabolic status with the reproductive axis.
Leptin is also formed in the placenta and is widely expressed in fetal tissues. It is important for placentation and maternal-fetal nutritional regulating growth and development (21). It stimulates hematogenesis and angiogenesis indicating a possible role in development.
Adiponectin
Adiponectin is another important adipocytokine that influences insulin sensitivity and atherogenesis. Adiponectin mediates its effect through binding to receptors AdipoR1 and AdipoR2, leading to activation of adenosine monophosphate dependent kinase, PPAR-α, and other yet-unidentified signaling pathways (22). Lower levels of adiponectin in obesity have been associated with insulin resistance (23), dyslipidemia (24), and atherosclerosis (25) in humans. With weight loss, plasma adiponectin levels significantly increase in parallel with improvements in insulin sensitivity (26). Impact Of Obesity On The Development Of Endocrine Disease Essay.
Adiponectin also suppresses the action of inflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha) (27), favorably modulates natural killer cell function (28) and other immune regulatory molecules (29), and improves dyslipidemia (30) and other risk factors of cardiovascular disease (27).
In addition to an anti-atherogenic effect, adiponectin may also have a variety of anti-tumor effects. This effect of adiponectin is thought to be mediated, in part, through inhibition of leptin induced tumor proliferation (31). It retards the aggressiveness of tumors and their metastatic potential of tumors and hypoadiponectinemia have been associated with a several cancers including breast, gastric, lung, prostate and others (32-35).
Chemerin
Chemerin, also known as Retinoic Acid Receptor Responder Protein 2, is among the newly discovered adipokines. Chemerin is secreted from mature adipocytes and is thought to play an important role in the regulation of adipogenesis as well as macrophage infiltration into adipose tissue (36). Recently published data suggest that chemerin may serve as an independent marker in diagnosing these conditions even before they become clinically evident (37).
Omentin
Omentin is an adipokine preferentially produced by visceral adipose tissue that exerts insulin-sensitizing actions (38). Its expression is reduced in obesity, insulin resistance and type 2 diabetes. Omentin is also positively related with adiponectin, high-density lipoprotein levels and negatively associated with body mass index, waist circumference, insulin resistance, triglycerides and leptin levels (39). Omentin has anti-inflammatory, anti-atherogenic, anti-cardiovascular disease and anti-diabetic properties (39). Regarding its effects in the cardiovascular system, omentin causes vasodilatation of blood vessels and mitigates C-reactive protein-induced angiogenesis. The ability of omentin to reduce insulin resistance in conjunction with its anti-inflammatory and anti-atherogenic properties makes it a promising therapeutic/diagnostic target (40). Impact Of Obesity On The Development Of Endocrine Disease Essay.
Retinol Binding Protein-4 (RBP-4)
RBP-4 belongs to the lipocalin family transporting small hydrophobic molecules and is produced primarily in the liver and mature adipocytes (41). Although the relationship between serum RBP-4 and obesity in humans has not been confirmed yet in population studies, several studies have shown a positive correlation between the expression of RBP-4 and BMI and glucose concentration (42). RBP-4 levels can be reduced by weight loss, balanced diet and exercise in association with increased insulin sensitivity (43, 44).
Visceral adipose tissue-derived serpin; serpin A12 (Vaspin)
Vaspin is a serine protease inhibitor produced by subcutaneous and visceral adipose tissue. Vaspin is also expressed in the skin, hypothalamus, pancreatic islets, and stomach. Vaspin is considered as an anti-atherogenic insulin-sensitizing factor (45).
Adipocyte Fatty Acid Binding Protein (A-FABP)
A-FABP is one of the fatty acid-binding proteins isoforms expressed adipose tissue and macrophages (46). It binds to hydrophobic ligands such as long chain fatty acids and facilitates their transport to specific cell compartments. Several studies have shown positive correlation between A-FABP and proinflammatory factors, such as CRP, and may also have significant importance in predicting insulin resistance (47).
Acylation Stimulating Protein (ASP)
ASP is synthesized and secreted by adipocytes and plays a major role in fatty acid uptake and triglyceride synthesis in these same cells, including postprandial clearance of triglycerides (48). It has been show to induce glucose-stimulated insulin release from pancreatic beta cells, modulates cytokine synthesis by mononuclear cells, as well as inhibits cytotoxicity of natural killer cells (49).
Renin-Angiotensin-Aldosterone System
Several components of the renin-angiotensin system (renin, angiotensinogen, angiotensin-converting enzyme and angiotensin II receptors) are expressed by the adipose tissue (50). Recent studies have shown that adipocyte deficiency of angiotensinogen prevents obesity-induced hypertension in male mice (51). Adipocytes promote obesity-induced increases in systolic blood pressure in male high fat-fed C57BL/6 mice via angiotensin 2 dependent mechanism (52). Adipocyte angiotensinogen deficiency prevents high fat-induced elevations in plasma angiotensin 2 concentrations and therefore in systolic blood pressure (51). These results suggest that adipose tissue serves as a major source of angiotensin 2 in the development of obesity-related hypertension. Impact Of Obesity On The Development Of Endocrine Disease Essay.
Others Factors Secreted by Adipose Tissue
Other proteins secreted by adipose tissue include plasminogen activator inhibitor-1 (PAI-1) (53) as well as complement factors adipsin, apelin, and pten, which may have roles in the pathophysiology or the progression of coronary artery disease and type 2 diabetes (54-56).
Interleukin-6 (IL-6) is released by macrophages and T-cells in the adipose tissue (57) and has been implicated in regulating insulin signaling in peripheral tissues by promoting insulin-dependent hepatic glycogen synthesis and glucose uptake in adipocytes (58). Recent studies show that IL-6 deficient mice develop late-onset obesity as well as disturbed glucose metabolism (59). The mechanisms underlying the effect of IL-6 on body fat and metabolism are not completely understood. However, IL-6 may exert central effects to decrease fat mass as a result of increased energy expenditure. Administration of IL-6 to the CNS has, for instance, been shown to induce energy expenditure and reduce fat mass more effectively than peripheral treatment (59). It has been suggested that IL-6 potentiates the action of leptin providing a possible mechanism for its anti-obesity effect (60). In addition, IL-6 has been linked to the increased inflammatory state seen in obesity. IL-6 and its subsequent inflammation have been postulated to play an etiologic role in the increased risk of thromboembolism observed in obese patients (61). Impact Of Obesity On The Development Of Endocrine Disease Essay.
