Dr. Robert Woodbury recently wrote an article, published in the Sonoma Medicine Magazine called “Emerging Concepts of Obesity”. It is an in-depth coverage of a complex topic with new perspectives on a major public health issue. Read and learn!
Emerging Concepts of Obesity
Robert Woodbury, MD, FACS
Northern California Medical Associates Sutter Metabolic and Bariatric Surgery Center Healthy Steps Therapeutic Lifestyle Center
…The only thing we know for certain about the disease of obesity is that we in the medical profession have spent the past 30+ years working in relative scientific darkness, and generally failing our patients suffering from a life threatening disease. This is shocking when we consider that the disease affects 78 million Americans, including 12.5 Million children, and costs society 147 Billion dollars per year! 1
In this issue of Sonoma Medicine the focus is on medical controversies. I was honored to be asked to write an article on the disease of obesity, and treatments. It was tempting to just answer the usual questions such as what diets we recommend, and how do we get patients to follow them, the role of surgery, and why our program is successful for both surgical and non-surgical patients. However, these are all the wrong questions.
Here are the the questions we should be asking:
- Why do mammals subjected to bariatric surgery lose drastically more weight than apair-mate mammal fed the same calorie restricted diet that the surgery animal ate?
- Why does a patient suffering from gastric cancer undergo a gastrectomy and roux-enY reconstruction not lose massive amounts of weight from the surgery?
- Why does a rodent fetus genetically designed to be immune from obesity, transplantedinto a morbidly obese mother, become morbidly obese?
- Why does a patient given certain probiotics lose more weight after bariatric surgery?
- If restricting calories were a dominant mechanism for weight loss why did the old jawwiring surgeries, and non-metabolic gastrectomies fail to cause real sustained weightloss?
- Why do malabsorptive bariatric operations cause profound anorexia, decreased foodintake, and increased energy expenditure when malabsorptive diseases, and massive small bowel resections, cause an increase in hunger, an increase in food intake, and a decrease in energy expenditure?
- If environment and family influences are to blame for obesity, then why do children born to mothers after bariatric surgery have less obesity, diabetes, and cardiovascular risk than their sibling born before mom had bariatric surgery?
• If gluttony is simply due to a deficiency in will-power why do bariatric surgery patients develop profound changes that immediately correct it?
If the reader is willing to dive into the topic, read on as I try to convey some of what I have learned after 19 years as a student of the disease. I view obesity through the lens of metabolic and bariatric surgery, which is the only effective treatment for patients suffering from the extreme end of the disease spectrum. If I can convince the reader that the disease is far more complex than a calorie intake problem and exercise deficiency, then I will have succeeded in my endeavor. Here we go……
Obesity is fundamentally a disease of energy imbalance, with one subsequent manifestation being excess energy storage. To achieve weight loss we must ultimately create negative energy balance. Historically we have only looked at the restrictive side of this equation with various low calorie diets schemes, and the expenditure side only in terms of exercise and activity. While not technically incorrect it is a very incomplete paradigm, and has led to decades of reliable treatment failure. To begin our understanding of the disease I will describe an elegant experiment I first learned from Drs Seeley and Kaplan and others at the Metabolic Applied Research Strategy 2 3 meetings I attend.
The experiment starts with a genetic strain of normal body weight rats which are allowed ad lib eating from “rat chow”. Over the adult life, the population will slowly increase body fat at a “normal” rate, by a few percentage points, with total final weights being remarkably similar among members of the population. Next we take a sample of the same rat strain and subject them to calorie restriction as part of an “under-fed “ cohort. Predictably they will all lose weight, at remarkably the same rate, with high loses in lean body mass. Eventually the weight loss will stop, the group will plateau, and then, despite continuing the calorie restriction, they will actually begin to gain weight back at the same “normal” rate as the control population, but with lower absolute weight levels. Once the calorie restriction is lifted and the rats are fed rat ad-lib, the entire population will rapidly gain weight, and then plateau at the same weight as the control population. Next we consider a cohort of rats that are force fed, called the “over-fed” group. This group will gain weight rapidly, then plateau despite the continued over- feeding. They will then resume the same slow rate of continued weight gain that the control rats exhibited. Once the rats are fed ad-lib, they will choose to eat only modest amounts of food, and rapidly drop fat mass. They will plateau at the same weight as the
control group. They will then slowly gain weight at the same “normal” slow rate as the control group.
When the hormonal profiles and energy expenditure of the under-fed vs the over-fed groups are compared we find a very different profile. Historically we in the medical profession have been trying to design a better plan for the “under-fed” state. Instead we need to find a way to create the physiologic profile of the “over-fed” state, which results in natural shedding of excess energy storage.
A math exercise will reveal the bottom line of the energy balance problem. An energy mismatch of 11Kcal per day is a 0.4% error, and will increase body fat by approximately 45 pounds over an adult life. A mismatch of 30Kcal per day is a 1.5% error and results in a 200 pound increase over an adult life. Correction of these small but powerful errors is the goal of treatment.
The story of genetics and obesity begins in 1999 with the discovery of the FTO gene. Its significance would be revealed in 2007, when one of the Genomic Wide Association Studies (GWAS) of the human genome and chronic diseases was published. It showed a relationship between the FTO genetic locus and adiposity of the subjects. 4 Over the next several years a series of independent studies would all corroborate this genetic locus and the predisposition to obesity 5 6 7 8 9.
The next breakthrough was published in 2013 10. Researchers from the United Kingdom, Germany,and Japan analyzed 359 normal weight young volunteers of mixed european descent.They studied body composition, the FTO genotype, serum ghrelin response, and brain responses to food cues. The study shows a link between the FTO gene, Ghrelin, and alterations in psychologic functions that are linked to obesity.
In considering genetics we must also consider the role of “epi-genetics”. Wikipedia provides a nice accurate description:
Epigenetics is the study of heritable changes in gene activity that are not caused by changes in the DNA sequence; it also can be used to describe the study of stable, long-term alterations in the transcriptional potential of a cell that are not necessarily heritable. Unlike simple genetics based on changes to the DNA
sequence (the genotype), the changes in gene expression or cellular phenotype of epigenetics have other causes, thus use of the term epi- (Greek: επί- over, outside of, around) -genetics.
An example of epigenetics is a study of mice cloning and embryo transplants 11. Researchers from the University of Cincinnati and Hawaii examined B6C3 mice. Compared to natural B6C3F1 offspring, the B6C3F1 mice cloned from in-vitro culture were born at a normal size but then developed obesity that was NOT due to excessive calorie intake and hyperphagia. A subsequent experiment showed that the F2 offspring created from natural mating of B6C3F1 mating produced normal weight offspring. The reader should realize that all of the mice in this study had exactly the same genetic code. The obesity, or lack of obesity was related to changes in the epigenetic state, presumably due to the intrauterine environment, which caused changes in the phenotypic expression.
Genetics vs Environment
It is always difficult separating out genetics and environment, but we do have some clues. Canada provides us with several findings from a longitudinal human study on the effects of in-utero environment 12 13. A health registry was kept of children born before their mother’s had bariatric surgery compared with sibling born after. One hundred thirteen obese mother were studied. One hundred and seventy-two children born after bariatric surgery were compared to 45 children born before. Eighty-eight percent long term follow up was achieved. There were no under-weight births. The prevalence of obesity was three times lower in children born after mothers achieved a healthy weight. The prevalence of severe obesity was 45% lower. Age for age they were leaner, and pound for pound there was less diabetes, hypertension, and hyperlipidemia. Plasma studies showed improved insulin sensitivity, improved lipid profiles, lower CRP, and improved profiles of leptin and ghrelin. One may postulate that the mother (hopefully) made significant lifestyle changes associated with the surgical treatment, and perhaps that was why the children were healthier. Unfortunately, any such environmental benefit was not transmitted to the children born before surgery.
I myself have an example of such a family. The child born after I performed mom’s surgery is indeed immune to the obesogenic environment that is associated with morbid obesity in all of his older siblings. While there is no doubt about the role of environmental factors in the disease, we cannot ignore the strong role of genetics and epigenetics.
The Gut Microbiome
I first took serous notice of this topic in 2009 when I read a study by a friend and colleague, Dr John Morton, from Stanford14. He and his team randomized bariatric surgery patients to probiotics vs placebo with the idea of looking for effects on vitamin absorption and GI quality of life. To quote the study; “surprisingly, the probiotic group attained a significantly greater percent excess weight loss”. In fact, the probiotic achieved a 9% increase in weight loss versus the placebo!
Germ-free mouse strains and fecal transplants of gut flora have further elucidated the association of the gut microbiome and weight loss. Fecal transplants from RYGB mice into obese germ-free mice cause significant fat loss15. There are strains of germ-free mice that even when fed extremely poor diets that mimic our obesogenic “western” diet, they still remain lean, and free of any insulin resistance. When these mice are colonized with the gut flora from normal weight, “normal flora” mice, they gain a small amount of “normal” weight. When they are colonized with the gut flora from obese mice, they become obese16.
The net effect of the gut microbiome on energy balance is well illustrated in one study from the NIH17. The residual energy in the feces of lean and obese individuals was examined. Ingesting different calorie loads produced a rapid change in the gut flora. In lean individuals, as the caloric load was increased, the stool energy loss was increased. This effect was not seen in obese subjects. Changes were seen in ratios of firmicutes to bacteroides, and “energy harvest” was increased by 150 Kcal. Here the reader should recall that a 30 Kcal/day mismatch in energy expenditure results in morbid obesity.
In summary, the effects of the gut microflora include changing energy harvest from food, changing fat storage physiology, changing insulin effects directly and via incretin effects, and altering systemic inflammation. Brain psychology is also affected. More information is surely coming in the literature. Dr Morton has counseled our metabolic group to remember that once upon a time peptic ulcer disease was an “acid problem” to be treated with surgery (I remember those days), and later with anti-acid medications. Today we understand it as an “infection” with H.pylori that is treated with antibiotics.
Gastrointestinal Hormones and Leptin
The gastrointestinal tract taken as a whole is an extremely powerful endocrine organ that influences appetite, and energy balance. For patients suffering from morbid obesity some of these GI hormones are severely deranged compared to normal weight patients.
Below I will briefly summarize some of the prominent points from two well done reviews18 19 .
Leptin is an adipokine secreted by fat cells, and technically not a gut hormone. However, it is so strongly linked to signaling food intake, energy expenditure, fat storage and insulin response, we will consider it here with the true GI hormones. As body fat stores increase so do the leptin levels. In a well functioning metabolism this sends a satiety signal to the hypothalamus, and increases energy expenditure via the sympathetic system, and thermogenic centers in the brain. During underfeeding, leptin levels fall, and the body “protects” itself from weight loss. A problem occurs with chronic overfeeding as the system can become “leptin resistant” in the same way as it becomes insulin resistant. The body will now mistakenly “protect” itself during periods of underfeeding, despite the total energy surplus.
Ghrelin, also known as growth hormone releasing factor, is an extremely powerful orexigenic (hunger) hormone. It is primarily secreted from the stomach, with minor amounts coming from the pituitary gland, intestine, and pancreas. Ghrelin secretion varies throughout the day, with levels falling after meals, then rising in anticipation of the next meal. In addition to stimulating appetite, ghrelin provides some inhibition to the visceral nervous system which blunts sympathetic increases in energy expenditure. Additionally, it affects fat by stimulating adipogenesis and inhibiting apoptosis of adipocytes. For reasons unknown, in patients suffering from chronic obesity, food intake does not suppress the ghrelin response as strongly as normal weight patients.
Peptide YY (PYY) is derived from cells in the distal intestine, and is released after feeding, in proportion to calories ingested. It then activates anorectic receptors in the Pro-opio-melanocortin-center (POMC) in the brain. to increase satiety. It also slows gastric emptying, as well as other actions. Obese patients have lower baseline levels of PYY, and also show a blunted response to feeding. During calorie restriction PYY levels fall even further, again “protecting” the body from fat loss.
Glucagon-like polypeptide 1 (GLP1) is secreted from the intestine and is part of the “ileal brake” system, slowing GI transit and function. It is also a powerful incretin causing improvement in insulin function, and pharmaceutical analogues are used to treat diabetes mellitus. Studies of GLP-1 receptor knock-out in mammals show glucose intolerance not related to eating behavior20. In the energy balance equation GLP-1 interacts with centers in the brain to increase satiety, decrease appetite, and may cause taste aversion. After roux-en-Y gastric bypass GLP-1 levels rise significantly. This may
be a dominant mechanism in how the procedure causes remission of diabetes even in non morbidly obese patients21.
There are several other well described hormones that one can investigate further if desired. It cannot be overemphasized that once the patient is in an obese homeostasis, any efforts at simple calorie restriction will cause the gut-brain axis to “protect” itself from fat loss22. Any successful treatment of obesity must address this fact. Metabolic and bariatric surgery directly “improves” many of these hormones and this is the primary mechanism of action. Certain nutritional manipulations are also effective, although not nearly as powerful as metabolic surgery.
Stress, Inflammation, and the Fat Mass
First we must make a distinction between subcutaneous white adipose tissue (WAT), and the visceral WAT that is drained via the portal system. The subcutaneous WAT can generally be thought of as a “safe” place to store energy. It easily absorbs energy, and more importantly, easily releases it. Like all fat, the subQ WAT expands via cellular hypertrophy but is also now known to be capable of expanding it’s energy storage capacity by cell division. This hyperplasia is protective when called upon to store large amounts of energy. The subQ WAT fat mass also has a low level of endocrine activity. We have all seen this patient who carries most of the excess weight in a gynecoid pattern, and who is surprisingly free from diabetes, hypertension, and other metabolic disease.
In contrast, the portal visceral WAT is extremely hormonally active. It is not capable of hyperplasia, and is not efficient at releasing it’s stored energy. Under extremes of energy storage demands, these adipocytes can actually outgrow their ability to extract sufficient oxygen. Cellular hypoxia and death occur, with release of multiple pro- inflammatory cytokines all well described by Dr ORourke and others23. We have all seen this patient with a central, android obesity pattern, that even with modest excessive weight has extremely high rates of metabolic co-morbidities.
Interleukin 1 is a prototypical inflammatory cytokine. Research from the University of Colorado has shown a link between IL-1 Beta, stress, and visceral obesity24 . In the setting of acute stress IL-1B provides support for the fight or flight response by facilitating mobilization of energy stores, increasing leptin, and augmenting glucocorticoids. However, with chronic elevation it becomes maladaptive, causing
impairment of insulin function, blunting of the satiety effect of Leptin, and inhibition of Lipoprotein lipase which then impairs mobilization of fat stores. IL-1B is also 5x more active in the subcutaneous WAT, and “poisons” its ability to store energy.
In putting it all together, chronic stress causes elevated glucocorticoids which raises blood sugar, and insulin levels. In the absence of immediate physical activity, the excess energy then requires storage. With a poorly functioning subcutaneous WAT, much of the energy is sent to the visceral WAT. Adipocyte hypoxia and other stress cytokines further add to the global state of hyper inflammation. Additionally, normal brain functions of satiety are impaired. When I discuss this fact with patients during their lifestyle program, we note that this effect is so powerful there is no negotiating our way out of it, no pill that can blunt it, and no surgery that can cure it. We also discuss the role of exercise in burning the mobilized energy from stress, as well as providing psychologic relief.
One of my diabetic non-surgical patients is a great illustration of this phenomenon. Even though food logs remain constant, and total weight remains constant with BMIs of 28-30, we see notable fluctuations in body composition analysis, and blood sugars become very difficult to control, in direct response to predictable cycles in work stress.
The central nervous system is where everything comes together. There is no psychology without biology, and no biology that is not affected by psychology. The brain receives inputs from the GI tract concerning nutrient status as well inputs from the gut microflora. Adipokines and myokines provide direct inputs into the status of energy storage and demands. Leptin, insulin, and gut hormones influence the brain’s long term regulation of feeding and energy expenditure 25. Hunger, satiety, and anorexia are all balanced. Below I will borrow from other authors 26 27 28 29, and review a few of the key brain areas.
One of the important centers in the brain is the pro-opiomelanocortin (POMC) system, especially MC4 receptors. Its role is illustrated by humans with mutations in the system who become morbidly obese starting in childhood. Animal models of POMC also show immediate development of morbid obesity. Additionally, animal models of roux-enY gastric bypass show that if MC4 receptors in the brain are knocked out, then the animal will be “immune” to the weight loss effects of the surgery
I believe that the medical profession, and society in general, underestimates the power of the brain. People suffering from obesity are believed to have a deficiency in will- power, rather than having a profound derangement in hunger and satiety signals. Certainly gluttony and other eating disorders do play a role, but they are not the complete story, and perhaps not even the dominant part. Most of my metabolic bariatric surgery patients are miraculously “cured” of their will power deficiency after surgery. Older bariatric surgical stomach stapling and jaw wiring procedures only provided restriction to food intake, and failed precisely because they had no metabolic effects. Those early surgeries unfortunately did not “cure” the patient of their “will-power deficiency”.
The full description of the treatment of obesity is not possible in this brief overview. Suffice it to say that the treatment of obesity must “convince” the body to stop “protecting” it’s fat stores, and promote a drop in it’s set point. We must abandon the idea of simple drastic calorie restrictions that will only cause metabolic responses that fight fat loss. We need to create a metabolic profile similar to the over-fed rat we learned about, that naturally sheds its excess fat. When we understand the extensive compensatory mechanisms in energy balance we realize that treatment must be multi- factorial, and must occur all at once in a coordinated effort. The environmental influences need to be blunted. Food prescriptions must be viewed as creating a series of cell signaling interactions with a defined metabolic outcome. For example we can use the glycemic load to change resting energy expenditure 30 and alter GI hormonal responses. Stress must be managed. The psychology of depression and gluttony must be improved. And of course, calorie intake must be dropped and exercise and activity increased.
Metabolic and bariatric surgery is one of the tools in the treatment armamentarium. In addition to restricting intake, surgery causes profound metabolic effects including increases in resting energy expenditure31, increases in fecal energy loss32, improvement in GI hormonal profile, alterations in the gut microbiome, and altered brain signalling. This allows a patient to consume 400-500 Kcalories per day and lose 2-3+ pounds of fat per week. In some patients diabetes may resolve immediately. Other co-morbidities also quickly improve.
When the global treatment plan all comes together for a patient, members of my team tell me they see it the moment the patient walks in the door. Energy is up, mood is improved, sleep is improved, patients report they “feel better”, and the results on our bioelectric impedance analysis show a drop in fat mass, and improvement in inflammation. Not infrequently my team even hears the complaint that we are making them are “eat too much”, even as we see 1+ pound per week fat losses without surgery, and without hunger. These results show us that the lifestyle phase of treatment is working. For morbidly obese patients we then add metabolic bariatric surgery to everything else they are doing. For those patients who have suffered from chronic pain from carrying 50-150+ pounds around 24 hours of every day, with the fear of diabetes and death from cardiovascular disease, and living with the shame of being too large in a society quick to judge, the results can be truly life-changing.
1 Centers for Disease Control. Obesity trends 2010
2 Ryan, Woods, and Seeley “Central nervous system mechanisms linking consumption of palatable high-fat diets to the defense of greater adiposity” Cell Metab. 2012 Feb 8;15(2) 137-149.
3 Seeley et al “Behavioral, endocrine, and hypothalamic responses to involuntary overfeeding.” Am J. PHysiology, Sept 1996 vol 271. 819-823.
4 Williams Trust Case Control Consortium. “Genomic-wade association study of 14,000 cases of seven common diseases and 3000 shared controls”. Nature 2007; 447: 661-678
5 Frayling et al. “A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity”. Science 2007. 316. 889-894
6 Cecil JE. “An obesity associated FTO gene variant and increased energy intake in children” NEJM 2008: 359: 2558-2566
7 Diva, C. “Variation in the FTO contributes to childhood obesity and severe adult obesity”. Nat. Genet. 2007: 39; 724-726
8 Andreasen, CH. “Low physical activity accentuates the effect of the FTO rs9939609 polymorphism on body fat accumulation”. Diabetes 2008; 57: 95-101
9 Hunt, SC. “Association of the FTO gene with BMI”. Obesity Apr 2008 16(4) 902
10 Karra et al. “A link between FTO, ghrelin, and impaired brain food-cue responsivity.” J. Clin. Inv. Aug 2013 123(8) 3539-3551
11 Tamashiro et al. “Cloned mice have an obese phenotype not transmitted to their offspring.” Nat Medicine Mar 2002 8(3)
12 Smith, Marceau, et al. “Effects of maternal surgical weight loss in mothers on the intergenerational transmission of obesity”. J. Clin Endocrinol Metab. 2009 94(11) 4275
13 Kral, Marceau et al. “Large maternal weight loss from obesity surgery prevents transmission of obesity to children who were followed for 2 to 18 years”. Pediatric 2006 Dec 118 (6) e1644
14 Woodard, Morton, et al. “Probiotics improve outcomes after Roux-en-Y Gastric Bypass surgery: A prospective randomized trial. “ J. Gastrointest Surgery 2009 13:1198-1204
15 Lio, Kaplan et al. “Conserved shifts in gut microbiome due to gastric bypass reduce host weight and adiposity”. Sci Transl Med 2013 5:178
16 Molinaro et al. “Probiotics, prebiotics, energy balance, and obesity”. Gastroenterol Clin N Am 2012 (41)843-854
17 Jumperts “Energy balance studies reveal associations between gut microbes, caloric load, and nutrient absorption in humans. “ Am J Clin Nutr Jul 2011 94(1):58-65
18 Jayasena et al “Role of gut hormones in obesity”. Endocrinology and Metabolism Clinics of N AM 2008 37: 769-787
19 Mikalakis and le Roux “Gut hormones and leptin: Impact on energy control and changes after bariatric surgery – what the future holds. “ Obes Surg 2012 22: 1648-1657
20 Gallwitz and Schmidt “GLP-1 receptor knock-out causes glucose intolerance but no alterations of eating behavior”. Z Gastroenterolgy 1997; 35: 655
21 Cohen et al. “Effect of gastric bypass surgery in patients with type 2 diabetes and only mild obesity”. Diabetes Care 2012; 35(7) 1420-1428
22 Sumithran et al. “Long term persistence of hormonal adaptations to weight loss”. NEJM 2011 365(17) 1597-1604
23 ORourke,Robert OHSU. Presentation at ASMBS 2012. Based on his article. O’Rourke “Inflammation in obesity-related disease. Surgery 2009 March; 145(3) 255-259
24 Speaker and Fleshner. “Interleukin-1 Beta: a potential link between stress and the development of visceral obesity. BMC Physiology 2012 12:8
25 Ahima et al. “Brain regulation of appetite and satiety”. Endocrin Metab Clinics N. Am. 2008 (37)811
26 Mikalakis and leRoux. “Gut hormones and leptin: Impact on energy control and changes after bariatric surgery, what the future holds.” Obes Surg 2012 22:1648-1657
27 Seeley and Kaplan. Presentation at Metabolic Applied Research Strategy Conference June 2010
28 Kaplan. “Effect of surgical and non-surgical weight loss on energy expenditure”. Presentation at Metabolic Applied Research Strategy, June 2012. Based on much of his own unpublished and published work including: Mirshahi et al “The MC4R Allele is associated with better metabolic status and more weight loss after gastric bypass surgery. J Clin Endocrin Metab Dec 2011; 96(12) E2088-E2096
29 Hatoum et al. “Melanocortin-4 receptor signaling is required for weight loss after gastric bypass surgery” J. Clin Endocrinolgy Metab 2012
30 Periera, et al. “Effects of a low glycemic load diet on resting energy expenditure and heart disease risk factors during weight loss. JAMA. Nov 24, 2004. vol 292 #20
31 Stylopoulous et al “Roux-en-Y gastric bypass enhances energy expenditure and extend lifespan in diet-induced obese rats”. Obesity 2009; 17(10): 1839-1847
32 Shin et al. “Longitudinal assessment of food intake, fecal energy loss, and energy expenditure after roux-en-y gastric bypass surgery in high fat fed obese rats.” Obesity surg Apr 2013; 23(4) 531-540