Links To And Excerpts From “Obesity: a 100 year perspective”

Today I review, link to, and excerpt from Obesity: a 100 year perspective [PubMed Abstract] [Full-Text HTML] [Download Full-Text PDF]. Int J Obes (Lond). 2024 May 7. doi: 10.1038/s41366-024-01530-6. Online ahead of print.

All that follows is from the above resource.

This review has examined the scientific basis for our current understanding of obesity that has developed over the past 100 plus years. Obesity was defined as an excess of body fat. Methods of establishing population and individual changes in levels of excess fat are discussed. Fat cells are important storage site for excess nutrients and their size and number affect the response to insulin and other hormones. Obesity as a reflection of a positive fat balance is influenced by a number of genetic and environmental factors and phenotypes of obesity can be developed from several perspectives, some of which have been elaborated here. Food intake is essential for maintenance of human health and for the storage of fat, both in normal amounts and in obesity in excess amounts. Treatment approaches have taken several forms. There have been numerous diets, behavioral approaches, along with the

development of medications.. Bariatric/metabolic surgery provides the standard for successful weight loss and has been shown to have important effects on future health. Because so many people are classified with obesity, the problem has taken on important public health dimensions. In addition to the scientific background, obesity through publications and organizations has developed its own identity. While studying the problem of obesity this reviewer developed several aphorisms about the problem that are elaborated in the final section of this paper.

International Journal of Obesity; https://doi.org/10.1038/s41366-024-01530-6

INTRODUCTION

The history of obesity over the last 100 or more years has been an exciting time for those of involved in the field. The scientific

underpinnings have increased dramatically and therapy has

improved beyond belief, particularly in recent years. This review is divided into 3 main parts. The first part is a review of major events that underpin our current knowledge base over the past 100 plus years. The second part will be the organizational

developments as obesity came of age and developed mono-

graphs, scientific organizations and journals to reflect this interest. The third part will be lessons learned over the years about obesity and how they summarize the field.

SCIENTIFIC BASIS FOR UNDERSTANDING OBESITY DEVELOPED OVER THE LAST TWO CENTURIES

Definitions and measurement of obesity

Although obesity is an excess of body fat, its measurement and

quantification took many years to develop. The publication in

1835 by Quetelet [1], a 19th century polymath, of his book on

measurements of human beings (Sur L’Homme) marked the

introduction of a term later called the Body Mass Index (originally Quetelet’s Index) which rose to prominence in the mid and late 20th century [2,3,4]. This index was his mathematical derivation of the best way to relate weight to height while minimizing the effects of height and is calculated as weight (in kg) divided by the square of the height (in meters). Over the next century a large number of other indices came into use, but the Quetelet or Body Mass Index (BMI) received a major push forward when Keys andhis colleagues compared several height/weight indices to direct measures of body fat in many populations and concluded that the BMI was to be preferred [5]. Prior to the adoption of the BMI actuarily based Life Insurance Company tables of desired weight were widely used by the public. When examined, it turns out that the range of weights in the widely used Metropolitan Life Insurance Table of mid-20th century had a range of weightexpressed as BMI units between 19 and 24 kg/m2. A BMI from 19 to 24 was initially proposed as a range for “healthy”weight [6]. A shift to the range of 20–25 as a range for recommended weight was suggested by Garrow as one that was easier to comprehend[7]. It was soon adopted as the criterion for evaluating population weight status and led to identification of the rapid growth in BMI after 1975 [8] and the obesity pandemic.

Among the deficiencies of the BMI was that it didn’t measure fat

directly and didn’t identify fat distribution nor provide insight into the mechanisms for developing obesity [3]. The work of Jean Vague (see below) in mid-20th century highlighted the importance of fat distribution as a cardiometabolic risk factor [9]. It was soon shown that waist circumference was a better index of risk than BMI [10]. The insurance industry had pointed out as early as 1904 that body fat located around the waist was hazardous to health just as was excess weight [11]. It was the work of Vague in France fifty years later that highlighted this risk. He showed that individuals with centrally located fat or upper body fat were at greater risk of cardiometabolic diseases than those with a lower body fat distribution [12,13]. Waist circumference proved to be a good index of central fat as did the ratio of the waist divided by the hip circumference and the waist circumference divided by the height. Larson et al and Bjorntorp both corroborated the findings of Vague [12,14,15].

Assessing total body fat also took a new turn with the work of

Behnke, Feen and Welham [16] who introduced hydrostatic

weight (weight on land vs weight when submerged) as a way to

calculate a 2-compartment model of lean body mass and body fat mass. The discovery of X-rays by Roentgen in 1895 [17] paved the way for the use dual-energy X-rays (DXA) to assess body composition with a 3-compartment model of bone, body fat and lean body mass. Other techniques such as computed

tomography which also used X-rays were developed and applied to the study of body composition. Magnetic resonance images provided similar detailed pictures of body composition, but without the exposure to ionizing radiation. Finally, techniques are currently being developed to determine body fat distribution from external body scans [18].

Fat cells as the energy storage receptables in obesity

Obesity, as already noted, is an excess of body fat. The extra body fat which reflects obesity is the result of a current or past positive fat balance which is reflected in both increased food intake and reduced physical activity. In an epidemiological study Church and colleagues showed that over the last 50 years in the U.S. daily occupation-related energy expenditure has decreased by more than 100 calories, and that this reduction can account for a significant portion of the increase in mean U.S. body weights for women and men. There is thus an important role of physical activity in the efforts to control the pandemic obesity [19]. which means that the individual with obesity is, or has been, in positive fat balance since adipose tissue is about 80% fat.

Fat cells are the vessels that store this fat. The idea that “cells”

were a basic unit of biology originated with Schwann [20] and

independently with Schleiden in the first half of the nineteenth

century. Hassall described the fat cell which has gone on to

become a central player in obesity [21]. In early life, proliferation of extra fat cells can lead to hyperplastic obesity [22]. Although the number of fat cells is relatively constant in adult life with a slow turnover rate, they can enlarge to store extra fat and often become insulin resistant in the process. The discovery that the fat cell could secrete a variety of products, often referred to as adipokines, led to the recognition of fat as a central organ in obesity. The idea that obesity is an ‘Adiposity-Based Chronic Disease’(ABCD) originated with the American Association of Clinical Endocrinologists [23] which focused additional emphasis on the importance of fat as did the discovery that it was the principal source of leptin a key regulatory hormone discovered by Friedman and Colleagues in 1994 [24] (see below).

Understanding the storage of nutrients as fat which increases

body fat stores began in earnest with the studies of Lavoisier and LaPlace [25]. They developed a calorimeter to measure the

thawing of ice during metabolism of a guinea pig and concluded

that “Respiration is then a combustion, very slow, it is true, but

otherwise perfectly analogous to the combustion of charcoal”[26]. This ‘oxygen theory of combustion’is the basis for energy turnover in the human body. Shortly after these discoveries Lavoisier lost his life to the Guillotine during the French Revolution. The next step forward was the publication more than 60 years later of the Conservation of Energy by Hermann von Helmholtz in 1847 [27]. This was followed some 50 years further on by the development of a human calorimeter by Atwater and colleagues who used it to determine that human beings followed the samelaws of heat conservation as other animals [28]. Metabolic chambers to study human beings have now become a major tool in the kit of scientists studying obesity in the 21st century.

The challenge of metabolic chambers is that they restrict the

activity of their occupants to a relatively small space and for a

relatively short time. Portable chambers worn on the back were

one attempt to escape this dilemma and there were many other

such efforts [29]. However, the development of doubly-labeled

water by Lifson and associated as a technique for measuring

energy expenditure in the living state provided a far better

solution [30]. It uses stable isotopes of water (²H2 18O) and

measures their dilution in body water produced by metabolism

over several days. One of the striking outcomes using this

technique was the discovery that adults who reported low calorie intake without losing weight tended to underreport their energy intake compared to the energy intake calculated from total energy expenditure and changes in body fat [31]

Phenotypes of obesity

The recognition that obesity was a multi-faceted disease occurred in the early 20th century. Although some individuals credit the recognition of hypothalamic obesity to Mohr in 1840 [32], I prefer to date it to the nearly simultaneous publication by Babinski in France and Frohlich in Germany of individuals who developed obesity in association with a hypothalamic disease [32,33,34]. This was followed a few years later by the description by the famous neurosurgeon, Harvey Cushing, of a patient with obesity associated with a pituitary tumor [35]. These 3 cases were followed by experimental studies of hypothalamic obesity in animals and human beings which continues to this day [32]. It illuminated the importance of hypothalamic centers identified initially as a ventromedial feeding center, and a more lateral hypothalamic satiety center.

A second major phenotype was the genetic forms of obesity in

animals and human beings [36] beginning with the description by Laurence and Moon [37] and then by Bardet in France [38], and independently by Biedl in Germany [39] of a clinical syndrome that came to be called the LMBB or Bardet-Biedl syndrome. Other clinical syndromes such as Ahlstrom’s and the Prader-Willi Syndrome were described later. Paralleling these clinical cases was the discovery of several forms of experimental obesity in mice and rats. In the yellow-obese mouse the coat color was linked to the fatness of the animal through changes in the melanocortin receptor system [40]. In the obese (ob/ob) [41] and diabetes (db/db) mouse [42] and the fatty (fa/fa) rat [43] obesity was a recessively inherited trait, with the defect being in either leptin deficiency (ob/ob mouse) or in the leptin receptor (db/db mouse and fa/fa fat). Leptin as a treatment for obesity in people with normal leptin levels was a failure, but it led to understanding how the arcuate nucleus in the hypothalamus coordinated the intake of food [44]. Clinically, however, leptin has proven useful in treating the rare patients with leptin deficiency and in the treatment of lipodystropic diseases [45].

There are both dominant genes with high expression levels like

leptin, and a much larger number of genes that have been

identified by using genome wide association studies, with both

BMI and waist circumference as major markers to which genes

were associated [46]. At present there are in the range of 1000

genes with variable contributions to the development of human

obesity and body fat distribution [46].

The body mass index (BMI) described above is also a phenotype

for obesity which was invaluable in tracking the epidemic of

obesity during the last 50 years. However, the BMI does not

provide information about fat distribution which is arguably more important than BMI as a predictor of outcomes associated with obesity. Nor does the BMI provide insight into the causes of

obesity [4]. The waist circumference or waist to height ratio are

more useful indices of central adiposity.

Healthy versus unhealthy obesity is another phenotype that has

been used to categorize obesity [47]. Using the features that define the metabolic syndrome including waist circumference

blood pressure, plasma glucose, plasma triglyceride levels and

levels of high-density lipoprotein (HDL-cholesterol) it is possible to categorize people into those with healthy obesity who have no

abnormal values and those with one or more abnormal values.

Those with Metabolically Unhealthy Obesity (MUO) are at higher risk of future cardiometabolic events. The limitation of this phenotype is that with time large numbers of those classified

with ‘Metabolically Healthy Obesity’will convert to the Unhealthy phenotype, although this can take many years.

Another phenotype is based on a functional classification

including such features as: [1]“the hungry brain”which can be

defined functionally as abnormal satiation; [2] emotional hunger or hedonic eating; [3] the “hungry gut”which was defined by abnormal satiety; [4] and finally “slow burn”which was identified as a decrease in metabolic rate [48]. The problem with thisapproach is that 15% of the patients included in one trial had none of these features and 27% had more than one. More research is clearly needed.

Food intake, behavior and obesity

Food plays a central role in the development of obesity –without

food we would starve to death. Interest in the mechanisms

controlling food intake has a long history [49], but I will start with the nearly simultaneous publication in 1912 by Cannon and

Washburn [50] and by Carlson [51] that hunger was precipitated by contractions of the stomach. Carlson in his 1916 review of theories of hunger divides them into 3 groups, those in which the information about hunger comes from stimulation of peripheral nerves; those in which the message comes from a hunger center located in the brain; and a third group involving both central and peripheral factors [52]. The importance of these peripheral factors has been strongly reinforced by showing that glucagon-like peptide-1 from the GI tract can reduce food intake [53] and that derivatives of this molecule can produce effective clinical agents for treating obesity. (See Drug Treatment below).

Food intake can be modified by the physiological and chemical

factors noted above, but also by behavioral means [54]. Pavlov in the early 20th century [55] showed that a dog could be

conditioned to eat by connecting the ringing of a bell with the

presentation of food. Several years later Skinner published his

observations that rewarding good behaviors would tend to

reinforce those behaviors [56]. In 1962, after World War II, Ferster et al provided a rationale for applying behavior to treatment of obesity [57] which was applied to the problem with great success by Richard Stuart in 1967. He reported weight loss which averaged 17.1 kg (37.75 lb) or 19.1% of the initial weight of 89.2kg [58]. The 8 women that were presented graphically in this paper ranged in age from 21 to 43, weighed between 178 and 222 pounds (80.45 to 100.9 kg) and lost 26 to 47 pounds (11.82 to 21.36 kg) over 12 months of therapy. These results stand out as one of the most successful uses of behavioral therapy in treatment of obesity. Behavioral techniques have subsequently become a major cornerstone of treatment for obesity. In the multi-center clinical trial called the Diabetes Prevention Program these techniques produced approximately 7.4% at one year and reduced the risk of developing diabetes by 58% in a group of patients with pre-diabetes [59]. Slightly better weight loss of 8.6% (8.7 kg) was obtained in Look AHEAD, another multi-center trial of weight loss in patients with established diabetes [60]. Behavioral treatments are thus an established portion of most comprehensive treatment programs.

Dietary approaches to obesity

Nutritional manipulation as part of the treatment of obesity can

be identified in all or almost all medical traditions [61]. From the

perspective of this paper, however, I want to begin with the

Banting Diet which carries of the name of the man who published it and who introduced a long history of “named”diets

to cure obesity [62,63]. Mr Banting was an undertaker of

prominence in London. As he grew wealthier, he also accumu-

lated more adiposity so that he couldn’t walk downstairs

frontwards. He consulted Dr. William Harvey (not the one who

discovered the circulation of blood) who was familiar with the

studies of Claude Bernard in Paris who had discovered that the

liver released glucose. Dr. Harvey recommended a “low

carbohydrate”diet to Mr. Banting [64] During the year he

followed this diet he lost more than 50 pounds and was so elated

that he self-published a short pamphlet on his diet in 1863. It

became a major success and spread worldwide and was

published in many languages and editions with the last one Icould identify being published in 1902 [62]

The success of the Banting diet and “Bantingism”as it was often

called, in the last part of the 19th century, led to an ongoing list of diet books designed to “cure”obesity often with special secrets in them [65,66,67]. One unfortunate outcome was the gelatin-based diet published by Linn and Stuart [68]. Even though a commission at the time of the French Revolution had shown that gelatin-based diets were incompatible with long life in animals [69,70], Linn andcStuart published the “Last Chance Diet”using a gelatin based formula. As might have been anticipated, at least 50 deaths were reported to the Food and Drug Administration (FDA) that were associated with cardiovascular arrhythmias in people using this diet [71]. At this point, the FDA stepped in and removed the diet from the market.

A new strategy appeared with the introduction of total fasting

and of very low-calorie diets [72]. The study of fasting in human

beings has a long history including the work of Benedict [73], Keys and colleagues during World War II [74] and Cahill and associates [75]. In the comprehensive study of fasting by Benedict [73,76]he estimated body fuels being used to sustain life when a professional faster starved for 28 days in a metabolic chamber. Glycogen stores were exhausted within 36 h. The excretion of nitrogen gradually fell. And the respiratory quotient (RQ) reached 0.7, indicating that fat had become the principle metabolic fuel. Metabolic rate also declined slightly. In 1931 Evans and Strang introduced what they called “A departure from the usual methods in treating obesity”based on their belief that “The treatment [of obesity] should be dietary, and dietary alone”[77]. They add to this their belief that “No special article of food has any merit with regard to losing weight. Total calories must be reduced.”With this background they ended up with a diet that has 8.5 kcal/kg, or about 400 total calories, as opposed to the usual diet containing

14–15 kcal/kg. This diet is within the range of “very low calorie

diets”which I define as between 201 and 800 kcal/d. After World

War II Bloom introduced total fasting as a treatment for obesity

[78].

Drugs used to treat obesity – some succeeded some not

Although the use of “medications”for obesity including emetics

and laxatives dates far back into the history of obesity [61], I will begin the story with the use of thyroid hormone in 1892 which had the rational basis of increasing “metabolism”[79] This was followed by 2,4-dintrophenol, a drug which “uncouples”oxidative phosphorylation in cells and which produced weight loss in munitions workers during World War I and was brought to the US by Tainter at Stanford in 1933. It received initial use until its toxicities became clear and the FDA, using newly granted powers, banned it in 1938. The third drug was amphetamine which appeared clinically in the 1930s and was shown to produce weight loss by Lesses and Myerson in a clinical trial in 1938 [80]. The addictive properties of amphetamine soon became evident, but this drug continued to be used especially after World War II as one ingredient in “Rainbow Pills”which were multi-colored capsules containing various combinations, d-amphetamine, diuretics, thyroid hormone, laxatives, phenolphthalein and various herbal

ingredients with other ingredients to mask some of the side

effects including digitalis, barbiturates, corticosteroids, potassium

and bella donna [81].

The wide-spread use of “Rainbow Pills”provided by various

pharmaceutical companies was one stimulus for founding of the

first association of physicians interested in treating obesity (see

below). The success of amphetamine as an appetite suppressant

also led to the search for non-addictive sympathomimetic

alternatives many of which were licensed in the US and other

countries during the period between 1959 and 1973 when the last

one was approved in the US.

The growing market of people with obesity after 1975 did not

escape the interest of the pharmaceutical companies. The

successes and failures of this endeavor have been chronicled

elsewhere [79]. In a review of drugs commissioned by the FDA in

1973, the Advisory Committee published the following list of

available sympathomimetic drugs (Table 1).

Approval of a new drug doesn’t guarantee its success or

durability. Several drugs that were approved were subsequently

withdrawn from the market. Here is a list of many of them (Table 2).

Against this pessimistic background are the encouraging

reports of treatments using glucagon-like-1 peptide agonizts that in some cases rival the success of bariatric/metabolic surgery discussed below. Gastrointestinal peptides have been of interest since the early 20th century [82]. Secretin and gastrin were two of the earliest GI peptides that were isolated. Cholecystokinin was shown to reduce food intake when infused into human beings [83] and later GLP-1 was also shown to decrease food intake when infused into human beings [53]. GLP-1 has a very short half-life in the circulation leading to the search for molecules that would have a longer half-life. Glucagon like peptide-1 is both an incretin which facilitates the release of insulin in the presence of glucose, reduces food intake and slows gastric emptying, thus making derivatives of this molecule effective as anti-diabetic and anti-obesity agents. Exenatide was the first commercial glucagon-like drug to be marketed and was followed by Liraglutide. Liraglutide

was effective in managing both diabetes and in treating obesity.

Following on its heels came semaglutide which had a longer half-life and was not only effective in treating diabetes, but also

producing significant weight loss [84] and in reducing the risk of future cardiovascular disease in high-risk patients [85]. This was followed by the even more dramatic weight losses associated with the use of peptides like tirzepatide, which had dual or triple action on GLP-1 receptors, but also GIP (glucose-insulin dependent peptide) and glucagon receptors [86,87]. These peptides were shown to be as effective in producing weight loss as the bench-mark weight loss with bariatric/metabolic surgery described below. Except for the high cost of these medications and the fact that weight is regained when they are stopped –drugs don’t work when not taken –we are entering a new era with a positive future.

Surgical treatments for obesity

The history related to surgical treatment of obesity is relatively

short only beginning in earnest after World War II ended in 1945

[88] In studies with dogs in 1954 Kremen reported that most of

the upper intestine could be removed or by-passed and still

preserve weight [89]. When the last part of the small intestine was

by-passed animals lost significant amounts of weight. Clinical trials

by Payne and DeWind in 1963 reported massive weight losses

after intestinal-colic by-pass operations that had to eventually be

reversed leading to the expected weight regain [90]. This was

followed by the jejuno-ileal by-pass which was popular during

much of the 1960s [91] In addition to its use as a treatment for

obesity it was also used in modified form to reduce cholesterol

absorption in patients with hypercholesterolemia [92]. The next

surgical procedure was the gastric-bypass by Mason and Ito in

1967 [93] which has continued to be a popular strategy.

Gastric-banding was the third procedure which consisted of an

inflatable band placed around the upper part of the stomach [94]. This procedure did not have sufficient sustained weight loss and has largely faded into obscurity. The surgical procedure called a “Sleeve Gastrectomy”which consists of removing the major curvature of the stomach and essentially elongating the esophagus now competes with the gastric by-pass which have both been aided by the development of laparoscopic techniques of performing these operations [95]. Finally, a variety of space- occupying balloons that could be inserted through the esophagushave been tested with variable success.

By their nature, surgical treatments carry higher risks to patients than lifestyle treatments for obesity. Several efforts have been made to compare the risk-benefit ratio for bariatric/metabolic surgery. There is convincing data that they are economically beneficial [96]. Data on the effects on health have taken years to unravel. Christou and colleagues published studies suggesting that bariatric surgery reduced both morbidity and mortality in operated patients [97]. Convincing data came from Lars Sjostrom and his colleagues who initiated a controlled study in the 1970s in which operated patients were matched on many traits to unoperated people with obesity [98,99]. Their prospective study used 3 operations: (1) the vertical gastroplasty; (2) the laparo-scopic banding technique; and (3) the gastric-bypass operation. In 1988 they published the first in a series of papers showing that mortality was significantly reduced in the operated individuals compared to the age, sex and weight matched un-operated controls [100]. This was followed over the next decade by many studies from this group showing that the risk of cardiovascular disease [101] and diabetes [102] were reduced and many patients experienced reversal of existing diabetes, something that had been shown earlier by Walter Pories et al who said as much in a provocatively titled paper “Who would have thought it? an

operation proves to be the most effective therapy for adult-onset

Diabetes mellitus”[103]