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Identifying the Causes: Genetics and Biomarkers of Obesity

  • Authors: Lisette Arnaud-Hevi, PhD; Clinton W. Wright, PharmD, BCPP
  • CME / ABIM MOC / CE Released: 8/2/2023
  • Valid for credit through: 8/2/2024, 11:59 PM EST
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This activity is intended for psychiatrists, primary care physicians, internal medicine specialists, nurses, and pharmacists.

The goal of this activity is for learners to be better aware of genetics and biomarkers for the diagnosis of obesity.

Upon completion of this activity, participants will:

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    • Genetics and biomarkers found in patients with obesity
    • Different specialties a patient should be referred to for diagnosis 


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  • Lisette Arnaud-Hevi, PhD

    Senior Medical Education Director - CNS
    Medscape, LLC
    New York, New York


    Lisette Arnaud-Hevi, PhD, has no relevant financial relationships. 

  • Clinton W. Wright, PharmD, BCPP

    Medical Education Director - CNS
    Medscape, LLC
    New York, New York


    Clinton W. Wright, PharmD, BCPP, has no relevant financial relationships.

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  • Stephanie Corder, ND, RN, CHCP

    Associate Director, Accreditation and Compliance, Medscape, LLC


    Stephanie Corder, ND, RN, CHCP, has no relevant financial relationships.

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Identifying the Causes: Genetics and Biomarkers of Obesity

Authors: Lisette Arnaud-Hevi, PhD; Clinton W. Wright, PharmD, BCPPFaculty and Disclosures

CME / ABIM MOC / CE Released: 8/2/2023

Valid for credit through: 8/2/2024, 11:59 PM EST




Clinton Wright (00:00): Yeah. Okay. Both are started. Lisette Arnaud-Hevi (00:03): Okay. Clinton Wright (00:03): Let's get crazy. Lisette Arnaud-Hevi (00:04): Fantastic. Welcome to this first podcast of a series of three, this title one entitled, Identifying the Cause of Genetic and Biomarker of Obesity. My name is Lisette Arnaud-Hevi. I'm a senior medical education director at Medscape, and joining me today is my colleague Clinton, who's a pharm D and also a medical education here at Medscape. Clinton, do you want to go through the main point we're going to be discussing today? Clinton Wright: Sure Lisette and it’s going to be a good time talking to you. So we're going be covering how obesity is currently defined. We’ll also talk about some of the etiology of the disorder as well as how to hopefully better define.. Let me start over Clinton Wright (01:01): Absolutely, Lisette. In this program, we'll discuss the following, how obesity is currently defined, what is the etiology of the disorder, and also how to identify the causes of the disorder. I'll get us started. Currently, we look at the definition of obesity through the lens of the BMI. The World Health Organization defines obesity as abnormal or excessive fat accumulation that presents a risk to health. A body mass index over 25 is considered overweight, and over 30 is obese. As a reminder, how we measure BMI is the weight over the height squared. If you're using the metric system, it's kilograms over meters squared. If you're using the English or US system, it can be pounds over inches squared, but you have to multiply by the number 703. Can you tell us, maybe, why this is problematic? Lisette Arnaud-Hevi (02:11): Yeah, I think we need to go back to what is the basis of BMI. It was devised in the 1830s by a Belgian astronomer. He was also a mathematician, a statistician, and a sociologist, but he was not a physician. So this BMI index we're all going by was not designed by a physician. This sociologist was trying to define the ideal average man, key emphasis on the word man. And this social idealization was also part of future eugenic studies. (02:53): So there is a lot of controversy around the BMI index, but one of the main problematic of it is that factors such as age, sex, ethnicity, and muscle mass can all influence the relationship between the BMI and the body fat. And so the problems with BMI is that it does not distinguish between excess fat, excess muscles, the bone density, and it does not provide any indication on the distribution of fat among an individual. We know just by looking at people basically that older adults tend to have more body fat than younger adults, women have greater amount of total body fat than men, although they might have equivalent BMI, and muscular individuals or highly trained adults may have a very high BMI because of increased muscle mass. And so if you look at a young, very athletic young man and a 65-year-old woman, they might end up having the same BMI, but have very different body composition, if I may say so. (04:19): BMI is not the ideal and I know that a lot of studies have been done to try to find a better way to assess excessive fat accumulation. One is the waist circumference, and both the World Health Organization and the NIH have come up with waist circumference measurement and definition. But we know that an increased risk of obesity is occurs in men with a waist conference circumference over 40" or 102cm, and in women with a waist circumference above 35", which is 88cm. And not only is the increased accumulation of fat in the waist a correlated risk for metabolic cardiometabolic disease, but it's also a question of where is the fat distributed? (05:25): We know that subcutaneous fat is less dangerous than visceral fat, and sometimes you have people that are, allegedly, very slim looking, but might have a lot of accumulated fat in the visceral part of their body and they might have a very increased risk for cardiometabolic disease. So subcutaneous white adipose tissue as an insulator can prevent heat loss, it's also a barrier against dermal infection, and it's a protective cushion against physical external stress. So it might be good to have a little fat under the skin in the belly area, just not too much. Clinton Wright (06:14): Okay. All right. Well, talking about it, what about pathology? I look at pathology as all about balance. It's both dysregulation of energy intake and dysregulation of energy expenditure. Energy and intake is regulated by ghrelin and leptin. Ghrelin stimulates the appetite while leptin signals the satiety, but they both have added effects. Ghrelin regulates sleep-wake rhythms, taste sensations, and glucose metabolism. Leptin regulates reproductive health, blood pressure, and immunity. So with those in mind, it can be hard to balance those two in certain. I want to start over on that slide. Lisette Arnaud-Hevi (07:08): Yeah. Clinton Wright (07:09): Yeah, we're okay. I'm still getting shit up from that cold last week. Okay. A little drink of water. Okay. (07:29): Pathology is all about balance. It's energy in, energy out. If we look at energy in, it's regulated by ghrelin and leptin. Ghrelin stimulates appetite and secondarily has an effect on regulating sleep-wake rhythms, taste sensations, and glucose metabolism. Leptin, which signals satiety, also also has plays a role in regulating reproduction, blood pressure, and immunity. We've looked at trying to manipulate each of those in a vacuum. Unfortunately with the secondary effects, it's a little bit hard. (08:13): I also wanted to point out, and I don't sure you’re aware of this, but there was a study published last week in Nature. One of the things that we know about this balance is that if we try to cut calories, the body responds by cutting metabolism. So it's hard to get too far down in our calorie count without having some compensatory mechanism that slows down our energy expenditure. Well, this study looked at the effect of recombinant growth differentiating factor 15 or GDF-15. It was in rodents and there was improvement in glycemic control through, and I'll give you all of it here, glial cell-derived neurotrophic factor family receptor alpha-like dependent suppression of food intake. That's the GFRAL. Basically what it showed is that in these animals we could decrease energy intake and we didn't have that secondary compensation, which then allows them to lose the weight. And so we really can be looking at this pathway in the future. Lisette Arnaud-Hevi (09:39): Full disclosure, this was done in rodents, so we need to see how applicable it is in the human. But I think you make a good point that looking for one cause, is it an increase in food intake or is it a decrease in energy expenditure, no matter what happens the body will try to reach a balance, and it might be a wonky balance, but this is what anybody is going to try to reach. Clinton Wright (10:12): Absolutely. I think the other thing we have to look at is really redefining obesity as a disorder. It's really multiple disorders or multiple touch points that we have to think about. We'll look at it as, possibly, an endocrine disorder because the adipose tissue is an endocrine organ. It could be classified as genetic disorder because we know that twin studies show that obesity is about 40-75% inherited. We might classify it in some of the mental disorders because there is an overlap in the polygenic risk associated with many psychiatric disorders and obesity. Or it could be a gut microbiome disorder or a GI disorder where we know that there's a simple role in signaling and fullness, but that microbiome probably plays more of a role in different areas of energy regulation. Lisette Arnaud-Hevi (11:23): So I think just calling something a patient obese without knowing which was the root cause of the obesity is quite problematic and we need to really look deeper in what might have caused the weight gain. As you were mentioning, one of the key points in weight gain might be an endocrine disorder. (11:54): Every single gland involved in the endocrine system might participate in the regulation of the metabolism, starting with the hypothalamus, where you can find orexin-A and orexin-B peptide, as well as their receptor, and they're responsible for the energy expenditure, so what we were talking earlier on. You have the thyroid, which is also involved in thermogenesis and potentially can suppress appetite. You have all the adrenal glands, and so we know that this is where cortisol is secreted from. We know that high stress and the increase in cortisol is linked with increase increasing abdominal fat and increased risk in cardiovascular disease. (12:52): We have androgenic excess in women that is also associated with expansion of visceral fat. The other side, in males, low testosterone has been as associated with energy imbalance, impaired glucose control, reduced insulin sensitivity, and dyslipidemia. We know also somatostatin is involved in the regulation of food-seeking behavior. Going down the body and all those endocrine components, pancreas is a key point for insulin secretion. We know that change in insulin and glucagon homeostasis can lead to increased risk of obesity. If we look at the gastrointestinal hormones, you mentioned leptin and ghrelin, but there is also secretin, there is also, as I was mentioning, somatostatin. All of these are involved in the digestions and the extraction of energy from the food. (14:00): Going down to the gonads, we mentioned androgen excess disorder in women, hypogonadism in men and low testosterone is associated with obesity. The first one you mentioned was the adipose tissue, and leptin is an anorexigenic peptide, which increases energy expenditure, but you also have other hormones secreted by the adipose tissue such as resistin and adiponectin that have been implicated in the pathogenesis of diabetic complications. So I think all the other point I wanted to bring up about, hormones is also that if you look at a person going through this cycle of life from puberty especially in women with the menstrual cycle and going further down with menopause, we know that at each step arms are going to be involved at puberty with the accumulation of fat that are participating in the development of distinctive sexual. Can I do that back? Clinton Wright:mmhmmm Lisette Arnaud-Hevi: So the one last point I wanted to bring up is that a person is gonna go through hormonal changes throughout their life, especially girls and women. If you look at from in men as well, No, I'm gonna do that again. The last point,… Clinton Wright: Yep. (15:36): The last point I want to bring is the cyclic impact of hormones. If you look at a person throughout their life, whether it's puberty, life, adult life, and menopause for women, you are going to have cyclic changes in hormones, as well as key cliff in changes or of hormonal level, and all of this will participate in changes in appetite and also fat accumulation. So the hormones are really a key point in the risk of obesity. Clinton Wright (16:20): Yeah, I think hormones are central to it. As well, we can look at genetic causes, and really if we look at genetic causes, I'm going to simplify it very much because it is a very complex relationship. There's really three areas. There's obesity-related genes and defects, for example, leptin, which is directly impacted or the receptor could be impacted. Then there's syndromic obesity and obesity-related syndromes. With syndromic obesity, that tends to be the primary effect is a change in weight, whereas we look at the obesity-related syndromes as being a cluster of symptoms with weight being one of them. Another area that I mentioned earlier is the relationship between psychiatric disorders and the increased risk of developing obesity as well as, I'll touch on in a minute, the effective antipsychotics, antidepressants, mood stabilizers, and other psychotropics on weight. (17:33): Real quickly, if we look at anxiety, we know there's an increased risk in panic disorder. Other disorders are not as well teased out. Personality disorders, there was a systematic review of 68 studies and showed that there was an odds ratio of 1.2 to 1.95 associated with personality disorders and obesity. Avoidant and antisocial related severity was associated with women and about a 38% risk for severe obesity in those two personality disorders. Eating disorder is very difficult because it is a disorder of eating, but what the researchers found was, over a 10-year period, it went from a 1% risk to about a 3.5% risk of accumulating weight. ADHD, definitely associated with adult persistent ADHD. In women, we see it related to remitted, persisting and lifetime. But the caveat here is that if you correlate for possible co-founders, it's really only significant for lifetime ADHD. Alcohol is real simple. Alcohol leads to obesity, but obesity does not lead to alcohol use. Depression, and we'll go into this more, it's bidirectional. Depression in obesity has an odds ratio of 1.3 to 1.4. Obesity in depression comes out at an odds ratio of 1.7. Clinton Wright: Sorry. Clinton Wright: okay, when we look at the cyber psychotropic medication effects, There's several things that are going on here at all at the same time. Looking at serious mental illnesses. Schizophrenia, major depressive disorder. They're about. Two to three times. Having let me start over again. Looking at seriously. 00:20:00 Clinton Wright: The blue parole is going to be fun. (20:07): Looking at serious mental illness, and by that I'm looking at schizophrenia, bipolar, and major depressive disorders, there's a two to three times higher mortality rate with about a 10 to 20-year reduction in life expectancy. Antipsychotics, antidepressants, and mood stabilizers impact obesity to varying degrees as well. The metabolic syndrome, which is related to use of some of these agents, which includes obesity, dyslipidemia, hypertension, and diabetes, are all affected at different levels by both the disease state and the medication that is used to treat that. (21:05): I'm looking forward to having a longer discussion with you on these aspects on our next episode. Let me say that one again anyway. Lisette Arnaud-Hevi (21:27): Thanks, Clinton. I think the fourth point we wanted to bring up into the potential causality for obesity was the importance of the gut microbiome. I think we are all aware of how important microbiota is important for digestions, vitamin synthesis, and metabolisms, but the gut microbiota is also key into regulating the food and the energy in intake for the body. And so, the gut microbiota can increase the energy production from food. It also provides low-grade inflammation and it can impact fatty acid and tissue composition. So it's quite important. (22:23): The importance of the gut microbiota is also learned from when it's not there anymore. We know that when there is a change in its composition due, for example, to increase or excessive use of antibiotic because the patient needed it, the gut microbiota is completely depleted, or there is a diet that have changed the gut microbiota, studies have shown that there is an increased risk of weight gain in patients who have imbalanced gut microbiome. (23:07): I think it's important to understand the cause to address the symptoms, and I think we should not limit the management of a patient with obesity to just their primary care physician. I think it's the primary care physician is extremely important to acknowledge when a patient is obese, but a larger team should be involved in there. Clinton, do you want to kind of go through that? Clinton Wright (23:40): Yeah. I think well not only the primary care physician, but I think when we get to the spectrum more to the schizophrenia side of things, that tends to be the psychiatrist. But those two are really crucial in coordinating the recognition of management obesity. But they can't do it alone. I think they need required specialists, obviously with endocrinology being such a large part, we need endocrinologists, and that may also lead to, if there's specific organs or systems involved, we might look at neurology, we might look at oncology, we might look at cardiology. (24:25): As I was saying, there's a large genetic load, and so a geneticist might get involved. I think where that's going to come into play is earlier on in a patient's life. For example, a patient and her child who is having difficulty feeding and failure to thrive, that turns around now they're 5 and they're starting to just gain weight, gain weight. I think we can suspect that there may be some genetic aspect to it. (24:57): Gastroenterologist, you mentioned the microbiota and depletion of it. We're looking at fecal microbiota transplants for C. difficile, but also I think we're looking at them now in patients who, we're still defining it, but we think have an altered microbiome. Certainly in the case of obesity, that may be a problem. Nutritionists, probably, they're going to need to be educated and involved, maybe at a higher level where they train clinicians of different specialties how to manage nutrition. (25:47): But I think two often overlooked professions that need to be brought into the fold are pharmacists and nurses. Pharmacists are really the gatekeeper of information out in the quote-unquote real world, and the nurses really are the key touchpoint for clinics. So they need to be prepared to answer questions from those patients that they have. Pharmacists as well are uniquely positioned to provide information about not only drug interactions, but drug-disease interactions that may be important. (26:33): Lisette, that's what I got there. Do you want to take us home? Lisette Arnaud-Hevi: Yeah, so just to conclude I think it's important to improve how health risk of weight gain is currently assessed, maybe stepping out of this BMI index and just looking at potentially more specific waist circumference a role into the healthcare. shreka music, I'm going to do it again. Lisette Arnaud-Hevi (26:47): Yes. Just to conclude, Clinton, I would say that improvement is necessary in how we are currently assessing the health risk of weight gain. Moving out of BMI, maybe, and going towards measuring waist circumference, understanding the etiology of a patients' weight gain. So whether it's an endocrine disorder, whether it's a genetic disorder, whether it's a mental health disorder, whether it's, potentially, imbalance in the gut microbiota or a combination of maybe multiple causes, it's important to look at different factors that might be involved into a person's weight gain. (27:59): As you were going through the list of all the specialties, I think in order to ensure durable weight loss, a team of specialty HCP should be involved. I think we gave you quite a wide list, but I think this would really help for a patients' overall health. Clinton Wright (28:19): Well, thank you, Lisette. It has been a pleasure chatting with you. Lisette Arnaud-Hevi (28:24): Likewise. Clinton Wright (28:24): I want to thank the audience for participating in this activity. Lisette Arnaud-Hevi (28:31): Thank you. Clinton Wright (28:33): Stop recording.
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