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This recent article takes a very complete look at the neurochemistry and neurobiology behind obesity in a better way than I’ve seen before. It also has a much more complicated model that, interestingly enough, also emphasizes how the system not only regulates satiety and hunger, but also regulates thermogenesis and basal metabolic rate as well as activity.
- Xu Yong, O’Malley Bert W, Elmquist Joel K. Brain nuclear receptors and body weight regulation. J Clin Invest. April 3, 2017;127(4):1172-1180. doi:10.1172/JCI88891.
This was later cited by an article on thyroid signaling.
- Kouidhi S, Clerget-Froidevaux M-S. Integrating Thyroid Hormone Signaling in Hypothalamic Control of Metabolism: Crosstalk Between Nuclear Receptors. Int J Mol Sci. July 11, 2018;19(7). doi:10.3390/ijms19072017. PMCID: PMC6073315. PMID: 29997323.
We all know that activity tends to decrease with obesity and it would be interesting if the same receptors that are involved in obesity are also involved in decreasing the desire for activity. That makes sense since, if the body is trying to conserve energy, it should both store the food it has for later and be less active.
This would also show that as the issues of obesity are resolved, patients show increased interest in activity. Although increased activity is not seen in everyone who loses weight, it is seen commonly after weight-loss surgery once a significant amount of weight is lost. We often assume that change is mostly due to the fact that they are carrying around less weight. However, it would be much more exciting to base that change not simply on mechanical issues, but actually on brain functioning issues.
It may also help explain why some people also engage in exercise and are thin. Perhaps the same mechanism is driving both. The issue may be that satiety and hunger are quite related to the interest in and or drive for exercise. And these are controlled centrally. An interesting concept to delve into!
This study shed some light on the genetics of obesity and the role of gene expression in the etiology of obesity:
- Oliveira BAP, Pinhel MAS, Nicoletti CF, et al. UCP1 and UCP3 Expression Is Associated with Lipid and Carbohydrate Oxidation and Body Composition. PLoS One. 2016;11(3). doi:10.1371/journal.pone.0150811
Their final point is UCP3 expression was associated with BMI, percentage of lean body mass (%LBM), and %FM in the postoperative period even after adjustment for age (Table 3). This simple diagram also helps explain.
Studies have suggested that genetic factors contribute to the development of obesity. Indeed, approximately 40–70% of the variation in susceptibility to obesity can be attributed to genetics.
Recently, four novel and heterozygous mutations in the UCP3 gene were identified (V56M, A111V, V192I, and Q252X) (Musa et al., 2012). Children carrying these mutations exhibited a higher percentage of fat and BMI, which was associated with dyslipidemia and lower insulin sensitivity (Musa et al., 2012).
Another article gives more insight.
- Musa CV, Mancini A, Alfieri A, et al. Four novel UCP3 gene variants associated with childhood obesity: effect on fatty acid oxidation and on prevention of triglyceride storage. Int J Obes (Lond). 2012;36(2):207-217. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3279655/. Accessed April 28, 2019 doi:10.1038/ijo.2011.81.
The fasting state probably reduces UCP1 expression even more, leading to even more efficiency (lower expression of UCP1). So, basically, with post-protein-sparing modified fast (PSMF) or weight-loss surgery, patients extract every possible value they can from the calories they eat due to down-regulation of UCP1. Down-regulation seems like the most obvious explanation for weight regain despite taking in the same amount of calories (the so-called “your body remembers its previous weight” comment is useless and oversimplified, since the body is not a memory circuit or a hard drive).
The article disagrees with that, and notes that they couldn’t identify a change in UCP1 expression. However, with an N of 13, it is pretty obvious in their diagram (see A for UCP1) that a larger study would likely find such a change in expression (or potentially, a small change is actually quite relevant). There is no way (yet) to induce UCP1 or UCP3 gene expression (though Vitamin D may help with UCP3 if it is low).
- Fan Y, Futawaka K, Koyama R, et al. Vitamin D3/VDR resists diet-induced obesity by modulating UCP3 expression in muscles. J Biomed Sci. 2016;23. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4966724/. Accessed April 28, 2019 doi:10.1186/s12929-016-0271-2.
Uncoupling proteins (UCPs) are members of the protein family located in the inner membrane of mitochondria. These proteins participate in energy expenditure, thermogenesis, regulation of free fatty acids, and reduction of reactive oxygen species.
UCP1 plays an important role not only in thermal regulation but also in energy balance and weight control. A recent study conducted on experimental models of bariatric surgery detected the presence of increased body temperature and up-regulated brown adipose tissue UCP1 protein expression levels after surgical intervention. In addition to its action in the adipose tissue, UCP1 contributes to the ability of the organism to oxidize substrates, metabolize lipids, and reduce weight, so high UCP1 expression should prevent the development of obesity.
UCP3 is also involved in energy metabolism regulation and weight control. Recent evidence has suggested that UCP3 plays an important part in modulating the use of lipid and glucose as an energy substrate. Gaining a better understanding of the role UCPs play in controlling and maintaining energy substrate oxidation could help to manage obesity.
The best solution is increased muscle mass that increases the total energy expenditure. Which leads to pumping iron in order to build up the TOTAL UCP3 gene expression (since most UPC3 is in muscle) and, since the UCP3 iw low due to gene expression and gene variants. UCP1 is in adipose tissue, so there is probably no hope. The UCP1/3 discussion also explains why rapid weight cycling is so bad and so consistently seen/experienced. Since there is nothing you can do to alter UCP1, adipose tissue is very effective at storing calories.
That means ANY transgression (e.g., eating more than usual, eating worse, not exercising) will result in fairly rapid storage of the excess calories as fat. Thus, lifelong and consistent (on a daily basis) change is valuable. Unlike (or actually like) sleep, a patient can’t make up for a setback by simply doubling down the next period. Stopping cravings and other interventions are still key.
But, in the long-term, obese folks need to boost their energy expenditure if they ever want to eat more than a fasting diet. And the only/easiest solution I see is to boost UCP3 through more muscle vs. ever more continuous training (see rats on treadmills), which is going to get more efficient over time and require more and more exercise as muscles and cardiovascular functioning get more efficient. Or perhaps high intensity interval training (HIIT) would be better.
One of my latest theories is that the real cause of the obesity epidemic is the variety of food currently available. Historically, there were not that many food choices. Now, we have an enormous amount of food choices, even in the healthy food category.
If you look at what diets are successful, potentially they’re all the same. What they do is limit the types of foods that you’re allowed to eat. That can be a Mediterranean diet or a ketogenic (low-carb) diet or a whole food, plant-based diet. Vegan diets work when folks cut out meat, but only when the person is also careful and thoughtful about the carbohydrates they cut out. When people go crazy eating all kinds of carbohydrates on a vegan diet, it stops working. But it doesn’t matter what diet is followed. All that matters is that the person rejected a substantial amount of the food choices available.
The other advice we hear now is for folks to cook their own food. Why would that matter? The food at home can be as (if not more) tasty than food acquired outside. And you make all the food you want when you cook. In fact, many of us cook more than we need so we have leftovers. So it doesn’t look like the quantity of food is the problem. What’s up? At home, you don’t have a menu and you probably only create a limited range of options (especially if one is cooking for one or two). So, the common recommendations for losing weight of “cook your own meals” or “pack your own lunch” are basically saying “limit your food choices.”
For that reason, any situation where there is unlimited access to food is a mistake. So, buffets, cruises, pot-lucks, and parties are obesogenic activities. As a society, we have to find a way we can have fun without including unlimited food options – unless we are happy with a world that increasingly looks like the movie, Wall-e.
Per that cruises link, here is some unscientific data to support the issue and some wrong advice from a well-meaning person.
According to the polls of several online cruise reviewers, it appears that the average weight gain on a 7-day cruise ranges from 5 to 10 pounds, depending on several factors such as amount of alcoholic drinks and workout frequency. If you are concerned about gaining weight, you should keep track of what you are eating, especially during buffet lunches and dinners, and what you are drinking, particularly sodas and alcoholic drinks. Also, make good use of the onboard exercise facilities, such as the swimming pool, gym, spa and running track (if available).
The advice is wrong. We know that you cannot “exercise off” pounds. A single cookie from Panera has enough calories for a strenuous 1-hour bike ride or a 30 minute 4-mile run. Neither option is really possible on a boat. Running around a flat track is mostly useless (no hills = minimal exercise) and, sadly, the continuous training components of gyms don’t provide much benefit (thus, resistance training is useful). And, of course, exercise makes one hungry. In a world of unlimited food, that hunger can quickly find a solution.
My argument above is that “keeping track of food” is not a strategy. When the brain sees food, it tells the body to eat it. For a cruise, to help folks maintain a healthy weight, it would need to provide a grocery store (not a grocery store that cooks meals, or “groceraunt”) and a kitchen to everyone. As a society, we are currently talking about sugar taxes. Maybe the problem with excessive food is that unlimited food options are too cheap, and we need to apply some behavioral economics to the challenge.
Bradley Tanner, MD, ME is a psychiatrist and Studio Head of HealthImpact.studio. In this role, he guides the development and evaluation of novel technological solutions to address health challenges including burnout, stress, and depression seen in medical students, residents, and practicing physicians in their early and later careers. You can reach Dr. Tanner at email@example.com. Personal health concerns and concerns related to suicidality should be addressed with your health professional.