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. Obesity is often a feature of polycystic ovary syndrome, but not a consequence of polycystic ovaries. Impact Of Obesity On The Development Of Endocrine Disease Essay.

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


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.


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. Impact Of Obesity On The Development Of Endocrine Disease Essay.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. 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.Impact Of Obesity On The Development Of Endocrine Disease Essay.  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.

Obesity is among the most common and costly chronic disorders worldwide. Estimates suggest that in the United States obesity affects one-third of adults, accounts for up to one-third of total mortality, is concentrated among lower income groups, and increasingly affects children as well as adults. A lack of effective options for long-term weight reduction magnifies the enormity of this problem; individuals who successfully complete behavioral and dietary weight-loss programs eventually regain most of the lost weight. We included evidence from basic science, clinical, and epidemiological literature to assess current knowledge regarding mechanisms underlying excess body-fat accumulation, the biological defense of excess fat mass, and the tendency for lost weight to be regained. A major area of emphasis is the science of energy homeostasis, the biological process that maintains weight stability by actively matching energy intake to energy expenditure over time. Growing evidence suggests that obesity is a disorder of the energy homeostasis system, rather than simply arising from the passive accumulation of excess weight. We need to elucidate the mechanisms underlying this “upward setting” or “resetting” of the defended level of body-fat mass, whether inherited or acquired. The ongoing study of how genetic, developmental, and environmental forces affect the energy homeostasis system will help us better understand these mechanisms and are therefore a major focus of this statement. The scientific goal is to elucidate obesity pathogenesis so as to better inform treatment, public policy, advocacy, and awareness of obesity in ways that ultimately diminish its public health and economic consequences. Impact Of Obesity On The Development Of Endocrine Disease Essay.

Essential Points
  • Obesity pathogenesis involves two related but distinct processes: (1) sustained positive energy balance (energy intake > energy expenditure) and (2) resetting of the body weight “set point” at an increased value. The latter process explains why weight lost through changes of diet and/or lifestyle tends to be regained over time, a major obstacle to effective obesity treatment.

  • How the increased body weight comes to be biologically defended remains uncertain, although ongoing research is beginning to shed some light on underlying mechanisms. Therapeutic strategies that target these mechanisms have the potential to reset the defended level of body weight at a lower, more normal value.

  • The impact of diet on obesity risk is explained largely by its effect on calorie intake, rather than by changes of either energy expenditure or the internal metabolic environment. Stated differently, “a calorie is a calorie.” Thus, habitual consumption of highly palatable and energy-dense diets predispose to excess weight gain irrespective of macronutrient content.

  • Beyond diet, environmental factors ranging from socioeconomic status to chemical exposures to sedentary lifestyle can confer obesity risk. How these inputs interact with genetic, epigenetic and developmental factors that predispose to obesity is a key question for future research.

The need to integrate molecular, genetic, developmental, behavioral, and environmental factors highlights the substantial challenge inherent in achieving a comprehensive understanding of obesity pathogenesis. Mechanistic formulations must draw from disciplines that include: the neuroscience of feeding behavior; the psychology of food reward; the metabolic impact of specific nutrients and changes of physical activity; as well as genetics, epigenetics, and developmental biology relevant to energy balance control, and the influence of exposure to environmental variables ranging from endocrine-disrupting chemicals (EDCs) to socioeconomic factors. When processing this information, one must also be mindful that although there are many interventions that can cause obesity in an experimental setting, the key question is whether they do cause obesity in a naturalistic environment. In this statement, we focus on factors for which compelling evidence exists that implicates them in the pathogenesis of either the accumulation or maintenance of excess body fat mass. Impact Of Obesity On The Development Of Endocrine Disease Essay.


Obesity is broadly defined as an excess of body-fat mass. Reliable fat-mass quantitation requires sophisticated tools that are not widely available (e.g., magnetic resonance imaging or dual energy X-ray absorptiometry), and this has hampered efforts to arrive at a more specific definition. Consequently, an elevated body mass index (BMI), which expresses body weight (in kilograms) as a function of body height (in meters2) as a surrogate measure of body fatness, is the most widely accepted definition of obesity. Population-based actuarial studies place the upper limit of normal BMI in adults at 25 kg/m2, define obesity as a BMI > 30 kg/m2, and designate a BMI between these values to be “overweight.” The degree of obesity can be further subcategorized into class 1 (BMI of 30 to <35), class 2 (BMI of 35 to <40), and class 3 (BMI of >40) (1). Assessing BMI in children requires adjusting for both age and gender.

BMI satisfies our need to estimate body-fat mass at a population level and thus gauge a group’s susceptibility to complications of obesity. However, it is not a reliable clinical tool for assessing individual body fatness, because variations in skeletal muscle and other lean-body-mass components create substantial variations in total body mass. For example, a heavily muscled individual with increased body weight relative to height will have a BMI value that can erroneously place them into the overweight or even obese category. Additionally, there are significant racial/ethnic differences in how BMI associates with adverse medical consequences. (For additional information, see the companion Endocrine Society Scientific Statement titled “Obesity Management: Past, Present, and Future; Science and State of the Art.”)

Rationale for a scientific statement on obesity pathogenesis

For most endocrine disease, researchers have established effective therapeutic treatments based on underlying disease mechanisms. This is not the case with obesity; unlike most other endocrine disorders, we have a very limited understanding of its pathogenesis, despite decades of research and billions of dollars spent each year on its treatment. This gross expenditure of time and money is undoubtedly linked to the extraordinarily high prevalence (affecting one-third of the adult United States population) (2), ease of detection, and stigma associated with obesity. These factors conspire to create an enormous demand for weight-loss products and services that continue to flourish, despite being largely ineffective, sometimes dangerous, and almost entirely unregulated (3). Impact Of Obesity On The Development Of Endocrine Disease Essay.

This situation is not unlike the medical practice of a century ago in which “glandular extracts” were cleverly marketed for a multitude of diseases, generating robust sales and profits for their manufacturers despite a lack of efficacy or safety data (45). It was largely in response to the rise of this practice (termed “organotherapy”) that the Endocrine Society chose a different path. In the third year of its existence, the Endocrine Society elected Sir Harvey Cushing as President. In his presidential address, he advocated strongly in favor of adopting the scientific method and abandoning empiricism to better inform the diagnosis and treatment of endocrine disease (6). In doing so, Cushing helped to usher in the modern era of endocrinology and with it, the end of organotherapy. (In an interesting historical footnote, Cushing’s presidential address was given in 1922, the same year that insulin was discovered.)

Clearly, we need a well-defined, generally accepted set of physiological, developmental, and environmental principles regarding body weight homeostasis that will inform strong research and therapeutic strategies regarding obesity pathogenesis. The current lack of consensus regarding obesity pathogenesis has resulted in competing and poorly justified claims both from within and outside of the scientific community. These inconsistencies erode public trust and confidence in the scientific process as it pertains to obesity and its treatment, which only further supports nonscientific ideologies and products. To break this vicious cycle, and to identify effective treatments, we need to establish clearly defined and reliable data regarding obesity’s underlying causes.

Energy Homeostasis and the Physiological Control of Body-Fat Stores
General principles

At its most basic level, the pathogenesis of obesity seems simple: Calories are consumed in amounts that exceed ongoing energy expenditure. Based largely on this concept, most people have historically perceived obesity as the result of negative personal traits, such as gluttony, sloth, self-indulgence, laziness, and lack of will power. However, growing evidence indicates that obesity pathogenesis involves processes far more complex than the passive accumulation of excess calories. It is this complexity that lies at the heart of why obesity is so difficult to treat. Fundamentally, humans have an “evolutionary physiology” that is predisposed to conserve body fat as a factor of survival. This evolutionary physiology in today’s climate of easy access to virtually unlimited calories has created a large segment of humanity that appears to be biologically predisposed to excessive weight gain. Hence, we see upward trends of adiposity in developed and developing communities.

How does the energy homeostasis system bear on this issue? We see clear evidence of a properly operating energy homeostasis system in the remarkable body-weight stability of individuals who are not obese over long periods of time. Evidence from an observational study of 15,624 healthy Swedish women (7) indicates that participants were, on average, >99.5% accurate in their annual matching of energy intake to expenditure for 10 consecutive years of observation. To better understand the implications of this observation, consider that a healthy adult weighing 165 pounds can be expected to gain >2.2 pounds in a year if they expend 27 fewer calories per day than they consumed. During 50 years of adulthood [assuming a caloric intake of 2500 kcal/day (46.6 M kcal total)], a weight gain of 1 pound (∼2270 kcal/pound mixed body tissue) per year (113,636 kcal total) is equivalent to a 0.24% positive caloric balance. Thus, we infer that such individuals are >99% accurate in matching energy intake to expenditure. There are caveats to such calculations relating to the fact that increased body mass increases energy expenditure (further reducing the balance error), but from a thermodynamic perspective, it is clear that obesity is generally the consequence of small, cumulative imbalances of energy intake and expenditure. Impact Of Obesity On The Development Of Endocrine Disease Essay. Although the causes of these imbalances can involve innumerable genetic, developmental, and/or environmental factors, once individuals who are obese and individuals who were never obese achieve their “customary” body weights and compositions, they tend to maintain and defend those weights by identical mechanisms.

Studies investigating the adaptive responses of normal-weight humans and animals to changes in body weight support the concept of a physiologically important energy homeostasis system. Weight loss induced by caloric restriction, for example, results in both an increased drive to eat and a reduction of energy expenditure. These responses both resist further weight loss and favor recovery of lost weight, and they can persist for years, provided that body-fat stores have not returned to baseline (8). These adaptive responses to weight loss are reported in both individuals who are obese and lean individuals (9), therefore suggesting that obesity pathogenesis involves the physiological defense of a higher level of body fat. This perspective offers a plausible explanation for the very frequent regain of lost weight that confounds most forms of obesity treatment (1011).

Conversely, normal-weight subjects respond to experimental weight gain (induced by “forced overfeeding”) by increasing energy expenditure and reduced hunger. Once forced overfeeding is discontinued, a combination of decreased drive to eat and increased energy expenditure tends to restore body weight to normal (9). Indeed, such overfeeding studies show that it is surprisingly difficult for normal-weight individuals to achieve and sustain experimentally induced weight gain (12). Individuals who are obese also resist excess weight gain induced by forced overfeeding (13). Therefore, their elevated levels of body-fat mass appear to be similarly subject to biological defense. Stated differently, individuals who are obese and individuals who are not obese appear to use the same homeostatic mechanisms to defend different levels of body-fat mass. This observation suggests that dysfunction of the energy homeostasis system is both necessary and sufficient for the biological defense of elevated body weight in individuals who are obese (14). What remains unclear is how this dysfunction is linked to factors that enable excess weight gain, such that excess body-fat mass comes to be biologically defended. This issue is central to obesity pathogenesis and therefore a central focus of this scientific statement. Impact Of Obesity On The Development Of Endocrine Disease Essay.

Leptin and energy homeostasis

The adipocyte hormone leptin, which circulates at concentrations proportional to body-fat mass, plays a significant role in the relationship between obesity and energy homeostasis. A deficiency of leptin causes severe hyperphagia and obesity in both humans and animals (15), with physiological leptin replacement ameliorating both the hyperphagia and obesity in leptin-deficient individuals (16). Therefore, there can be no question that normal body-weight maintenance in humans requires intact leptin-regulated neurocircuits.

However, these observations do not indicate that genetic deficiencies of leptin or its cognate receptor are important causes of human obesity. Although such individuals exist, they are rare (17). In contrast, most individuals who are obese have elevated plasma leptin levels (in proportion to the increase of body-fat content), raising the possibility that common forms of obesity are associated with “leptin resistance” (i.e.,that supraphysiological plasma leptin levels are required to overcome tissue resistance to leptin and thereby enable energy intake and energy expenditure to match one another). Because adipocytes secrete leptin in proportion to body-fat content, the only way to raise plasma leptin levels in this setting is to become obese.

These considerations would seem to point to a causal role for leptin resistance in the pathogenesis of common forms of obesity, but the matter remains unsettled. For one, there is no uniformly agreed-upon definition for leptin resistance (18), and the presence of hyperleptinemia per se cannot be taken as evidence of its presence. Indeed, recent data suggest that the cellular response to leptin (e.g., activation of intracellular STAT3 signaling) is preserved in obese, hyperleptinemic rodents (19). The circulating leptin concentration needed to fully engage central nervous system responses likely differs among individuals based on the influence of genetics, development, and possibly diet. Thus, some individuals who are obese may simply require more leptin (and hence body fat) to fully engage relevant neurocircuits (20).

Given the evolutionary considerations alluded to above, the primary role played by leptin-responsive neurocircuits may be related more to preventing loss of body fat (communicated to the brain by a decrease of leptin signaling) than to defending against its increase (conveyed by increased leptin levels). In this formulation, genetics, development, and even environmental factors can influence the level of leptin signaling (“threshold”) below which compensatory increases in food intake and reductions in energy expenditure occur. Accordingly, this theory holds that leptin circuitry is more sensitive to decreases than to increases in the circulating leptin level, with the limited response to leptin concentrations above the lower threshold offering a potential explanation for what some refer to as leptin resistance. The apparent resistance in this formulation is simply a reflection of the circuitry’s design (2021). More work in this area is clearly needed. Impact Of Obesity On The Development Of Endocrine Disease Essay.

Fuel partitioning, insulin, and obesity

General perspectives on obesity pathogenesis have swung from early conceptualizations of obesity as a storage disease of adipose tissue (analogized presumably to some of the earliest identified inborn errors of metabolism by Garrod) to more recent brain-centric models, in which the brain, by virtue of its operational control of food intake and energy expenditure, imposes excess calories on passive adipocytes. Sometimes referred to as “pull” and “push” models, respectively, each makes very different predictions regarding both underlying molecular mechanisms and how we should approach obesity prevention and treatment. Embedded within this debate is the extent to which adipocyte-autonomous processes can pull substrate molecules preferentially into adipocytes, and by “partitioning” calories in this way cause higher fractional deposition of calories as fat. A key prediction of this model is that some individuals who consume a diet in which caloric intake and energy expenditure are matched (e.g., an isocaloric diet) will preferentially deposit ingested calories as fat at the expense of their lean tissue mass, thereby becoming relatively fatter without entering a state of positive energy balance per se (see the section titled “Impact of diet composition on obesity risk”).

Although it is possible that variations in body composition among individuals of the same body weight reflect (to some extent) the consequences of such processes, achieving clinical obesity in this manner must be rare, because most individuals who are obese have absolute increases of both lean and fat mass. Nevertheless, when leptin-deficient ob/ob mice are pair-fed the same amount of food consumed by normal controls, they gain more mass (due to reduced energy expenditure) and preferentially deposit that mass as fat, leading to an absolute and relative deficiency of lean mass in these animals (22). Although the mechanism underlying this partitioning effect must relate to developmental and/or intercurrent effects of leptin (perhaps involving interactions with insulin as well), the precise biology is not clear (22). The hypothesis that leptin plays a direct role in these processes is supported by evidence of its direct effects on lipid partitioning in skeletal muscle (22).

Lipoprotein lipase (LPL), an enzyme that hydrolyzes circulating apolipoprotein-bound acylglycerides at the surface of many cell types (including adipocytes and myocytes), also appears to affect the partitioning of fatty acids in ways that affect both absolute and relative fat mass. Although mice overexpressing LPL in skeletal muscle accumulate triglyceride in muscle and are resistant to increases of adipose tissue mass during overfeeding (23), overexpression of LPL in adipocytes does not affect body weight or adiposity in mice (24). Restoration of muscle LPL in mice that otherwise lacks the enzyme creates animals functionally lacking LPL in adipose tissue; surprisingly, these mice are characterized by normal body-fat mass, apparently because of a compensatory increase of fatty acid synthesis in adipocytes (25). Expression of LPL varies widely by depot in humans, and it might account for differences in adipose tissue distribution in some individuals. As insulin increases the synthesis and activity of LPL (while also stimulating adipocyte uptake of fatty acids and glucose), intrinsic differences in insulin-mediated molecular processes could (in theory) play a determinative role in body-fat content and/or distribution. In this context, however, it is important to note that humans lacking LPL on a genetic basis have normal fat mass due to the ability of adipocytes and muscle to take up circulating free fatty acids in quantities sufficient to allow adequate aclyglyceride formation in adipose tissue or oxidation in muscle (26). Therefore, although local activity of LPL (in adipocytes and muscle) could play a role in partitioning of fat among tissues, it appears to be neither necessary nor sufficient for the uptake of fatty acids into adipose tissue.Impact Of Obesity On The Development Of Endocrine Disease Essay.


Several investigators have proposed that the effect of specific diet components on insulin secretion or action contributes to obesity pathogenesis through effects on calorie deposition in adipocytes, rather than (or in addition to) effects on energy balance per se. Essentially, carbohydrates in general (and refined and possibly naturally occurring sugars in particular) are proposed to promote hyperinsulinemia that in turn drives glucose and fatty acids into adipose tissue (25). Accordingly, this process is proposed to cause obesity by both direct effects on adipocytes that favor fat deposition and by lowering circulating metabolic substrates (and/or exerting effects on hepatic metabolism) that subsequently stimulate food intake. Additional “lowering” effects on energy expenditure by these dietary components are proposed to exacerbate the tendency toward increased fat deposition (27). As we discuss in greater detail in a later section (“Diet composition, lifestyle, and obesity risk”), this hypothesis remains controversial and has yet to receive the level of support needed for broad acceptance. Among several concerns is that differences in diet composition have yet to be convincingly shown to cause differences in body composition when provided in an isocaloric manner (such that total calorie consumption is matched between diets) (28). This is not to say that diets high in refined carbohydrate and/or fructose (soft drinks) do not predispose to obesity, but the underlying mechanism is likely to involve excessive intake of calories, rather than nutrient-specific or hormonal effects on substrate partitioning.

Collectively, these data suggest that diet composition per se (relative quantities and specific types of carbohydrates, sugars, and fatty acids, as distinct from caloric content) contributes far less to the etiology of obesity than do contributions made by the net imbalance of intake and expenditure. It therefore follows that although variations in diet composition can powerfully affect palatability and hence hedonically motivated feeding, whether it can also influence food intake via secondary metabolic consequences (e.g., effects of insulin on circulating nutrient levels) remains a highly controversial topic that seems unlikely to be resolved without clinical studies that will be costly and challenging to undertake. Impact Of Obesity On The Development Of Endocrine Disease Essay.


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