Tips Today The Example For The Nutrient Vantage Hypothesis Of Obesity, Business Office Ii
In this post, I'll explore whether or non the scientific evidence is consistent amongst the predictions of the nutrient vantage hypothesis, every bit outlined inward the terminal post.
Before diving in, I'd similar to address the critique that the nutrient vantage concept is a tautology or relies on circular reasoning (or is non testable/falsifiable). This critique has no logical basis. The vantage together with palatability value of a nutrient is non defined yesteryear its trial on unloosen energy intake or torso fatness. In the research setting, nutrient vantage is measured yesteryear the mightiness of nutrient or food-related stimuli to reinforce or motivate demeanor (e.g., 1). In humans, palatability is measured yesteryear having a someone gustation a nutrient together with charge per unit of measurement its pleasantness inward a standardized, quantifiable manner, or sometimes yesteryear looking at encephalon activity yesteryear fMRI or related techniques (2). In rodents, it is measured yesteryear observing stereotyped facial responses to palatable together with unpalatable foods, which are similar to those seen inward human infants. It is non a tautology or circular reasoning to enjoin that the reinforcing value or pleasantness of nutrient influences nutrient intake together with torso fatness. These are quantifiable concepts together with every bit I volition explain, their human relationship amongst nutrient intake together with torso fatness tin be, together with already has been, tested inward a controlled manner.
1. Increasing the reward/palatability value of the diet should displace obese gain inward animals together with humans
The most highly rewarding together with palatable rodent diet I know of is the "cafeteria diet", composed of human junk food. This diet is unmatched amid solid-food diets inward its mightiness to displace persistent overeating together with rapid obesity inward rodents, easily surpassing high-fat together with high-sugar diets, although these also displace obese gain to a lesser grade (3). Rodents volition voluntarily suffer extreme mutual depression temperature or human foot shocks to obtain this food, fifty-fifty when regular chow is freely available (4, 5).
Other diets that displace marked obesity inward rodents, such every bit chocolate Ensure together with sure purified high-fat diets, are highly preferred to normal chow. In my ain experience, rats really really similar the purified high-fat diet nosotros feed them to brand them obese. When you lot set a pellet of it inward their cage, they volition drib everything together with devour it immediately, fifty-fifty if they only finished a repast of regular chow together with fifty-fifty if it's inward the middle of the nighttime for them (the calorie-free cycle; they're nocturnal). If you lot drib a pellet of regular chow into their cage, they volition by together with large ignore it unless they've been nutrient deprived.
As I reported inward a previous post, exposing humans to a similar "cafeteria diet" causes overeating together with rapid obese gain every bit good (6).
Some people may object that these experiments are non properly controlled to create upward one's heed if nutrient reward/palatability are the critical factors, i.e., at that topographic point are multiple differences betwixt diet conditions. For the most part, that is true, together with nosotros volition receive got to sentiment these experiments every bit i imperfect brush stroke inward the overall painting. However, at that topographic point receive got been unopen to efforts to specifically isolate the effects of reward/palatability on obesity inward rodents. In i study, investigators added a multifariousness of flavor-enhancing substances to measure rodent pellets inward an endeavor to manipulate the diet's palatability without affecting nutritional factors, together with called this regimen the "isocafeteria diet" (7). Here's what they found:
2. Decreasing the reward/palatability of the diet should displace obese loss inward animals together with humans that carry excess fat
One of the most hitting weight loss studies I've seen was conducted inward 1965 together with involved feeding a bland liquid diet through a dispensing straw (12). Lean together with obese volunteers were instructed to consume every bit much of the liquid nutrient every bit they wanted, but they were permitted no other food. While lean volunteers ate a normal amount of calories together with maintained weight, obese volunteers dramatically reduced their spontaneous calorie intake together with lost obese rapidly, amongst i human losing 200 lbs inward 255 days without hunger. This is just what i would seem if unpalatable/unrewarding nutrient lowered the biologically "defended" bird of obese mass. Interestingly, the diet was high inward refined saccharify but was otherwise really depression inward palatability/reward value. Similar findings receive got been reported yesteryear other investigators (13).
Monotonous, bland liquid diets rest i of the most effective obese loss tools inward clinical practice. Similarly, diets that cut down major vantage factors without deliberately calling for calorie restriction, such every bit low-fat together with low-carbohydrate diets, all displace obese loss fifty-fifty though inward unopen to cases the diet changes that are implemented diametrically oppose i unopen to other (14, 15). The farther vantage is lowered, the to a greater extent than effective the diet is for appetite suppression together with weight loss.
Rodent studies are consistent amongst those inward humans. Returning rodents made obese using palatable high-fat diets or chocolate Ensure (or yesteryear gavage overfeeding) to ad libitum ordinary rodent chow makes them lose most of the excess fat, although unopen to of it is often retained (16, 17, 18).
None of these studies are sufficiently controlled to isolate vantage and/or palatability, thus they tin non yesteryear themselves testify the hypothesis, but they are silent consistent amongst it.
3. Individual sensitivity to nutrient vantage should predict time to come obese gain
I'm aware of 3 studies that receive got investigated this question. In the first, researchers found that the reinforcing value of nutrient relative to a non-food stimulus predicted obese gain over the side yesteryear side twelvemonth inward 7-10 twelvemonth quondam children (19). In the second, the responsiveness of reward-related encephalon regions to imagining palatable vs. unpalatable foods (as assessed using fMRI) predicted torso majority index (BMI) gains inward adolescent girls, together with this trial was modified yesteryear cistron polymorphisms inward dopamine receptor genes (20). The 3rd study also used fMRI to demonstrate that greater activation inward reward-related encephalon regions during exposure to appetizing nutrient cues predicted greater BMI gains over fourth dimension inward adolescent girls (21).
Consistent amongst other findings, these studies dot that heightened nutrient vantage sensitivity is a pre-existing province that predisposes to obese gain over fourth dimension inward susceptible people.
4. Brain circuitry that controls vantage together with hedonic processing should interact amongst circuits that influence nutrient intake together with torso fatness
The hypothalamus, which is the principal homeostatic regulator of torso fatness, together with reward/hedonic centers, part extensive together with reciprocal anatomical connections. One major pathway runs betwixt the nucleus accumbens (NAc), which is critical to vantage together with hedonic processing, together with the lateral hypothalamus (LH), which is critical both for reward/hedonic processing together with torso obese homeostasis (22). The role of the LH inward feeding together with vantage is illustrated yesteryear the fact that if you lot implant an electrode into a rat's LH together with allow the rat to self-stimulate, it volition do so compulsively every bit if it were administering a drug; LH stimulation also potently increases nutrient intake (23). Lesioning the LH causes a decrease inward nutrient intake together with obese majority (24).
The LH shares reciprocal connections amongst other hypothalamic regions of import for torso obese homeostasis such every bit the arcuate nucleus (ARC), together with thus is probable a node for the relay together with integration of information from homeostasis together with reward/hedonic systems. The ARC is a major CNS receptor site for circulating signals of unloosen energy status, specially leptin but also including insulin, ghrelin, amylin, glucose together with obese acids (25). It contains neuron populations (POMC/CART together with NPY/AgRP) that are critical for the command of nutrient intake together with torso obese mass. Manipulating the activity of these neurons profoundly influences nutrient intake together with obese majority (26, 27).
Reward, hedonic together with homeostatic systems are inward a tightly coupled CNS circuit, suggesting that they may reciprocally influence i another. Indeed, it is good established that homeostasis centers influence vantage together with palatability circuits, together with this is evident inward the fact that nutrient tastes improve when you're hungry than when you're total ("hunger is the best sauce"). The side yesteryear side department volition demonstrate that vantage together with hedonic circuits influence homeostasis circuits every bit well.
5. Manipulation of motivational together with hedonic circuits inward the encephalon (e.g., yesteryear lesion, drugs or genetic manipulation) should impact nutrient intake together with torso fatness
There is a tremendous amount of information related to this question, together with I don't intend this to hold out anywhere nigh a comprehensive give-and-take of it. Manipulating vantage or hedonic circuits tin receive got a profound impact on nutrient intake together with torso fatness. One instance is that inhibiting NAc rhythm out neurons using a glutamate receptor antagonist (DNQX) causes voracious feeding (28). The machinery involves the stimulation of feeding centers inward the LH together with ARC, demonstrating the functional importance of connections from reward/hedonic centers to hypothalamic centers regulating nutrient intake together with torso fatness (29, 30). Similarly, chemically lesioning the NAc rhythm out increases weight gain inward rats (31).
Opiate signaling inward the CNS is a critical ingredient of hedonic processing. Researchers receive got long recognized the mightiness of opiates to increment feeding, together with the mightiness of blocking opiate signaling to decrease feeding (31, 32, 33). Opiate signaling inward the striatum (particularly the NAc) increases the palatability of food, together with this trial depends mostly on the mu opioid receptor subtype (34, 35). The mu opioid receptor blocker naloxone specifically decreases the palatability of nutrient together with the consumption of palatable nutrient inward rats together with humans, but has picayune impact on the intake of less palatable nutrient (36, 37, 38). Mice that lack the mu opioid receptor cistron are lean together with resistant to diet-induced obesity, suggesting that opioid-mediated nutrient palatability may hold out a major portion of the argue rodents teach obese on refined high-fat diets (39). Activating opioid signaling inward the striatum does non increment the amount a rodent volition piece of work for food, does non increment repast frequency, together with does non reinforce behavior, thus striatal opioids regulate hedonic processing (liking) without affecting vantage (wanting) (40).
It has been demonstrated many times inward the scientific literature together with inward my ain hands that rats volition consume a substantial amount of palatable nutrient fifty-fifty after they receive got already eaten less palatable nutrient to fullness (41). This is the "dessert effect"-- you've only finished a large repast together with you're stuffed, but you lot care to "make room" for unopen to other 200 calories when the cake rolls around. This seems to hold out related to opioid signaling, every bit the activation of this organisation inward the striatum increases both the liking of foods together with repast size (42).
Dopamine is critically involved inward vantage functions, together with it turns out to hold out a major regulator of nutrient intake together with torso fatness every bit well. Injecting dopamine into the encephalon reduces nutrient intake, together with the primary site of activeness appears to hold out inward the LH (43). Dopamine signaling inward the striatum regulates the motivation to obtain food, but non the enjoyment or consumption of nutrient that is readily accessible (44). Thus, inward the striatum it impacts motivation/reward (wanting) but non palatability (liking).
Drugs that activate sure dopamine receptors tin displace compulsive overeating of palatable foods together with weight gain (45). However, the dopamine organisation is complex, involving multiple receptor subtypes that receive got unlike functions inward unlike encephalon regions, together with unlike drugs touching these subtypes differently. The dopamine D2 receptor inward detail seems to hold out involved inward nutrient intake together with torso fatness. The D2 receptor activating drug bromocriptine causes obese loss inward a multifariousness of animate existence models of obesity, including humans inward unopen to studies (46). Obesity is associated amongst reduced D2 receptor density inward the striatum, together with at that topographic point is evidence that reduced striatal D2 receptors tin precede the evolution of obesity (47). There is also evidence inward rodents that chronic exposure to highly palatable nutrient tin cut down D2 receptor density inward the striatum (48), suggesting that exposure to hyperpalatable foods, inward improver to genetics (discussed below), tin atomic number 82 to an obesity-promoting pattern of D2 receptor aspect inward the brain. This is portion of a broader pattern of addiction-like changes that prepare inward the brains of animals chronically exposed to hyper-palatable/hyper-rewarding food.
If the effects of opioid together with dopamine signaling on palatability together with vantage really influence nutrient intake together with torso fatness, together with so drugs that impact these systems should hold out able to displace obese loss inward humans. Such a drug exists-- it's called Contrave, together with it is a combination of naltrexone (an opioid receptor blocker that acts mostly at mu together with kappa receptors) together with bupropion (dopamine-norepinephrine re-uptake inhibitor). Contrave has shown effectiveness every bit a obese loss drug inward humans, although side effects receive got prevented FDA approval (49). The proposed machinery of this drug is via the indirect activation of POMC cells inward the ARC, over again suggesting that reward/hedonic circuits influence those that regulate torso fatness.
One of the most interesting links betwixt reward/hedonic circuits together with hypothalamic circuits is via endocannabinoid signaling. It has been known for unopen to fourth dimension that marijuana increases the consumption of palatable foods together with causes weight gain if smoked oftentimes plenty (50). Today, nosotros know that endocannabinoid signaling is intimately involved inward hedonic together with vantage circuitry. Marijuana acts principally via the CB1 receptor (51). Mice lacking the CB1 receptor cistron CNR1 are lean together with resistant to diet-induced obesity (52). The CB1 receptor blocker Rimonabant is an effective obese loss drug inward humans, together with its trial appears to occur mostly if non solely inward the encephalon (53, 54). Rimonabant is basically "reverse marijuana". Perhaps non surprisingly, it was pulled from the marketplace yesteryear the FDA due to negative psychological side effects.
It is no coincidence that ii of the most effective obese loss drugs developed inward recent history, Contrave together with Rimonabant, both target vantage together with hedonic centers inward the brain.
6. Genetic differences that influence vantage and/or hedonic circuits should correlate amongst differences inward torso fatness
Each someone on this world carries a unique combination of cistron variants, together with inward unopen to cases these influence physical characteristics together with the reply to environmental factors. Some of these variants are inside dopamine receptor genes, together with thus receive got the potential to influence nutrient reward. Several studies receive got shown that polymorphisms of the D2 dopamine receptor associate amongst the opportunity of drug addiction, gambling addiction, together with obesity (55, 56, 57, 58, 59, 60). Polymorphisms inward other genes that influence dopamine signaling, including the D4 dopamine receptor, the dopamine re-uptake transporter, together with catechol-O-methyltransferase, receive got also been found to associate amongst obesity opportunity (61, 62, 63, 64).
Polymorphisms inward the CB1 cannabinoid receptor cistron CNR1 also associate amongst torso fatness (65, 66). This is consistent amongst the fact that the CB1 receptor knockout mouse is resistant to diet-induced obesity, together with the CB1 blocking drug Rimonabant reduces torso fatness inward humans (67).
I receive got non come upward across whatever reports of opioid receptor cistron polymorphism frequency inward obesity.
These findings back upward the hypothesis that vantage together with hedonic circuits inward the CNS influence torso fatness, together with that the pre-existing characteristics of these circuits tin explicate differences inward the reply to rewarding stimuli, together with differences inward torso fatness, inward the full general population.
7. On a cultural level, obesity prevalence should rail amongst changes inward the reward/palatability value of prevailing diet patterns
The evidence inward this category is the to the lowest degree good controlled, since many things receive got changed during the evolution of the "obesity epidemic". However, for the hypothesis to hold out convincing, at a minimum it has to hold out consistent amongst how diets inward most cultures receive got changed every bit obesity has increased inward recent years.
The obesity epidemic inward the U.S. has paralleled a pregnant shift inward nutrient culture. Here are a few examples to illustrate the trends (68). In the terminal 50 years:
Similar trends are apparent inward all affluent nations every bit the nutrient chain has teach increasingly commercialized together with gradually displaced traditional nutrient culture, together with invariably this has been accompanied yesteryear increased torso fatness on a population level.
That's non to enjoin that commercial nutrient is responsible for all obesity. Obesity has been documented for thousands of years, if non longer, including inward sure cultures that only had access to traditional ingredients (e.g., Polynesian islanders). However, inward these cases (including Europe earlier industrialization), obesity was mostly restricted to affluent individuals who benefited from skilled chefs together with alternative ingredients, every bit good every bit a sedentary lifestyle.
Some people receive got brought upward the examples of French Republic together with Republic of Republic of India every bit challenges to the nutrient vantage hypothesis, stating that both receive got a tradition of delicious food. That, of course, is true. However, it's of import to scream upward that most people traditionally didn't consume foie gras together with obese spiced curries every day, together with nutrient that you lot consume inward a eating theatre or every bit a tourist doesn't necessarily correspond peoples' day-to-day nutrient choices. In France, which I tin talk for because I spent a pregnant chunk of my life there, most meals are composed of relatively simple, fresh, home-cooked food. This is specially truthful for the older generations. The nutrient is non depression inward fat, or depression inward animate existence fat. It tastes good, but it isn't extravagant. Traditionally, people rarely ate at restaurants, which were expensive together with considered a special treat. As the nutrient organisation has industrialized, together with commercial nutrient has increasingly replaced habitation cooking, the prevalence of obesity has increased.
I'm non every bit familiar amongst traditional Indian food, together with I don't desire to pose every bit an practiced here, but I'm quite confident that what nosotros run into inward restaurants together with cookbooks inward the U.S. is non what the average Indian someone was eating 50 years ago, together with for the most portion silent non today. The traditional Indian diet, earlier industrialization, differed yesteryear part but was by together with large really depression inward obese together with relied heavily on plainly starch foods such every bit rice, millet together with wheat. This was supplemented amongst to a greater extent than exciting dishes based on legumes, vegetables, dairy together with occasionally meat. But my agreement is that, for an ordinary meal, these were pocket-size portions compared to the plainly starches that formed the backbone of the diet. I dubiousness the average Indian someone 50 years agone was making complex dishes using liberal quantities of ghee together with a dozen spices for dinner every night, or deep frying things. Spices together with ghee aren't gratis together with cooking similar that takes time, science together with special equipment-- is it a priority if you lot don't receive got much disposable income?
As Republic of Republic of India has industrialized, together with the diet has teach to a greater extent than diverse, to a greater extent than fatty, to a greater extent than refined together with to a greater extent than commercialized, obesity throughout the province has increased (particularly abdominal obesity), together with Republic of Republic of India at nowadays has a serious diabetes together with coronary view affliction occupation on its hands.
Conclusion
If you lot made it this far, you're a hero! As you lot receive got seen, a publish of mutually buttressing lines of evidence, including controlled diet studies, observational studies, neuroscience, pharmacology together with genetics, back upward the hypothesis that nutrient vantage together with palatability influence nutrient intake together with torso fatness. It's non every solar daytime that you lot come upward across an thought inward the diet-health literature that is consistently supported yesteryear so many independent lines of inquiry. This hypothesis isn't really sexy, which is i argue why it hasn't gained every bit much traction amongst earth every bit sure other ideas, but I'm non every bit good concerned nigh that. I only desire to empathize what causes obesity, together with this hypothesis has a lot of explanatory power.
The grade to which nutrient vantage together with palatability receive got driven the modern obesity epidemic remains opened upward to interpretation. However, inward 2011, the evidence has accumulated to the dot where it is clear that they play a role. I side amongst modern nutrient vantage researchers inward thinking it is a major factor, although at that topographic point are for certain others.
Before diving in, I'd similar to address the critique that the nutrient vantage concept is a tautology or relies on circular reasoning (or is non testable/falsifiable). This critique has no logical basis. The vantage together with palatability value of a nutrient is non defined yesteryear its trial on unloosen energy intake or torso fatness. In the research setting, nutrient vantage is measured yesteryear the mightiness of nutrient or food-related stimuli to reinforce or motivate demeanor (e.g., 1). In humans, palatability is measured yesteryear having a someone gustation a nutrient together with charge per unit of measurement its pleasantness inward a standardized, quantifiable manner, or sometimes yesteryear looking at encephalon activity yesteryear fMRI or related techniques (2). In rodents, it is measured yesteryear observing stereotyped facial responses to palatable together with unpalatable foods, which are similar to those seen inward human infants. It is non a tautology or circular reasoning to enjoin that the reinforcing value or pleasantness of nutrient influences nutrient intake together with torso fatness. These are quantifiable concepts together with every bit I volition explain, their human relationship amongst nutrient intake together with torso fatness tin be, together with already has been, tested inward a controlled manner.
1. Increasing the reward/palatability value of the diet should displace obese gain inward animals together with humans
Baca Juga
The most highly rewarding together with palatable rodent diet I know of is the "cafeteria diet", composed of human junk food. This diet is unmatched amid solid-food diets inward its mightiness to displace persistent overeating together with rapid obesity inward rodents, easily surpassing high-fat together with high-sugar diets, although these also displace obese gain to a lesser grade (3). Rodents volition voluntarily suffer extreme mutual depression temperature or human foot shocks to obtain this food, fifty-fifty when regular chow is freely available (4, 5).
Other diets that displace marked obesity inward rodents, such every bit chocolate Ensure together with sure purified high-fat diets, are highly preferred to normal chow. In my ain experience, rats really really similar the purified high-fat diet nosotros feed them to brand them obese. When you lot set a pellet of it inward their cage, they volition drib everything together with devour it immediately, fifty-fifty if they only finished a repast of regular chow together with fifty-fifty if it's inward the middle of the nighttime for them (the calorie-free cycle; they're nocturnal). If you lot drib a pellet of regular chow into their cage, they volition by together with large ignore it unless they've been nutrient deprived.
Some people may object that these experiments are non properly controlled to create upward one's heed if nutrient reward/palatability are the critical factors, i.e., at that topographic point are multiple differences betwixt diet conditions. For the most part, that is true, together with nosotros volition receive got to sentiment these experiments every bit i imperfect brush stroke inward the overall painting. However, at that topographic point receive got been unopen to efforts to specifically isolate the effects of reward/palatability on obesity inward rodents. In i study, investigators added a multifariousness of flavor-enhancing substances to measure rodent pellets inward an endeavor to manipulate the diet's palatability without affecting nutritional factors, together with called this regimen the "isocafeteria diet" (7). Here's what they found:
It was demonstrated that the daily presentation of a novel alternative of the palatable foods which composed the “isocafeteria diet” led also to a sustained increment inward nutrient intake together with to overweight. Variety together with high palatability are per se sufficient factors to overcome regulatory mechanisms.This trial was partially replicated yesteryear a minute study that showed higher torso obese gain inward rats fed a nutritionally controlled diet high inward obese together with refined saccharify amongst a multifariousness of palatable flavorings added, compared to the same diet without flavors, although adding palatable flavors did non promote obese gain inward the context of a low-fat, low-sugar diet (8). Dr. Anthony Sclafani showed that manipulating the palatability of a sugariness solution (Polycose; similar to maltodextrin) using non-nutritive flavoring agents influenced obese gain inward rats exposed to it (9). In baboons, adding preferred but non-nutritive flavors to measure monkey chow increased nutrient intake together with torso weight (10). The investigators concluded:
These results dot that flavored chows may hold out useful for producing a nonhuman primate behavioral model of obesity together with for inducing animals to consume otherwise unpalatable diets.Many human studies receive got shown that people consume to a greater extent than nutrient at a sitting if the nutrient is higher palatability than if it is lower palatability (11). This is truthful fifty-fifty if palatability is manipulated using substances that receive got picayune or no impact on the nutritional character of the food, including saccharin (sweet), monosodium glutamate (savory) together with herbs/spices.
2. Decreasing the reward/palatability of the diet should displace obese loss inward animals together with humans that carry excess fat
One of the most hitting weight loss studies I've seen was conducted inward 1965 together with involved feeding a bland liquid diet through a dispensing straw (12). Lean together with obese volunteers were instructed to consume every bit much of the liquid nutrient every bit they wanted, but they were permitted no other food. While lean volunteers ate a normal amount of calories together with maintained weight, obese volunteers dramatically reduced their spontaneous calorie intake together with lost obese rapidly, amongst i human losing 200 lbs inward 255 days without hunger. This is just what i would seem if unpalatable/unrewarding nutrient lowered the biologically "defended" bird of obese mass. Interestingly, the diet was high inward refined saccharify but was otherwise really depression inward palatability/reward value. Similar findings receive got been reported yesteryear other investigators (13).
Monotonous, bland liquid diets rest i of the most effective obese loss tools inward clinical practice. Similarly, diets that cut down major vantage factors without deliberately calling for calorie restriction, such every bit low-fat together with low-carbohydrate diets, all displace obese loss fifty-fifty though inward unopen to cases the diet changes that are implemented diametrically oppose i unopen to other (14, 15). The farther vantage is lowered, the to a greater extent than effective the diet is for appetite suppression together with weight loss.
Rodent studies are consistent amongst those inward humans. Returning rodents made obese using palatable high-fat diets or chocolate Ensure (or yesteryear gavage overfeeding) to ad libitum ordinary rodent chow makes them lose most of the excess fat, although unopen to of it is often retained (16, 17, 18).
None of these studies are sufficiently controlled to isolate vantage and/or palatability, thus they tin non yesteryear themselves testify the hypothesis, but they are silent consistent amongst it.
3. Individual sensitivity to nutrient vantage should predict time to come obese gain
I'm aware of 3 studies that receive got investigated this question. In the first, researchers found that the reinforcing value of nutrient relative to a non-food stimulus predicted obese gain over the side yesteryear side twelvemonth inward 7-10 twelvemonth quondam children (19). In the second, the responsiveness of reward-related encephalon regions to imagining palatable vs. unpalatable foods (as assessed using fMRI) predicted torso majority index (BMI) gains inward adolescent girls, together with this trial was modified yesteryear cistron polymorphisms inward dopamine receptor genes (20). The 3rd study also used fMRI to demonstrate that greater activation inward reward-related encephalon regions during exposure to appetizing nutrient cues predicted greater BMI gains over fourth dimension inward adolescent girls (21).
Consistent amongst other findings, these studies dot that heightened nutrient vantage sensitivity is a pre-existing province that predisposes to obese gain over fourth dimension inward susceptible people.
4. Brain circuitry that controls vantage together with hedonic processing should interact amongst circuits that influence nutrient intake together with torso fatness
The hypothalamus, which is the principal homeostatic regulator of torso fatness, together with reward/hedonic centers, part extensive together with reciprocal anatomical connections. One major pathway runs betwixt the nucleus accumbens (NAc), which is critical to vantage together with hedonic processing, together with the lateral hypothalamus (LH), which is critical both for reward/hedonic processing together with torso obese homeostasis (22). The role of the LH inward feeding together with vantage is illustrated yesteryear the fact that if you lot implant an electrode into a rat's LH together with allow the rat to self-stimulate, it volition do so compulsively every bit if it were administering a drug; LH stimulation also potently increases nutrient intake (23). Lesioning the LH causes a decrease inward nutrient intake together with obese majority (24).
The LH shares reciprocal connections amongst other hypothalamic regions of import for torso obese homeostasis such every bit the arcuate nucleus (ARC), together with thus is probable a node for the relay together with integration of information from homeostasis together with reward/hedonic systems. The ARC is a major CNS receptor site for circulating signals of unloosen energy status, specially leptin but also including insulin, ghrelin, amylin, glucose together with obese acids (25). It contains neuron populations (POMC/CART together with NPY/AgRP) that are critical for the command of nutrient intake together with torso obese mass. Manipulating the activity of these neurons profoundly influences nutrient intake together with obese majority (26, 27).
Reward, hedonic together with homeostatic systems are inward a tightly coupled CNS circuit, suggesting that they may reciprocally influence i another. Indeed, it is good established that homeostasis centers influence vantage together with palatability circuits, together with this is evident inward the fact that nutrient tastes improve when you're hungry than when you're total ("hunger is the best sauce"). The side yesteryear side department volition demonstrate that vantage together with hedonic circuits influence homeostasis circuits every bit well.
5. Manipulation of motivational together with hedonic circuits inward the encephalon (e.g., yesteryear lesion, drugs or genetic manipulation) should impact nutrient intake together with torso fatness
There is a tremendous amount of information related to this question, together with I don't intend this to hold out anywhere nigh a comprehensive give-and-take of it. Manipulating vantage or hedonic circuits tin receive got a profound impact on nutrient intake together with torso fatness. One instance is that inhibiting NAc rhythm out neurons using a glutamate receptor antagonist (DNQX) causes voracious feeding (28). The machinery involves the stimulation of feeding centers inward the LH together with ARC, demonstrating the functional importance of connections from reward/hedonic centers to hypothalamic centers regulating nutrient intake together with torso fatness (29, 30). Similarly, chemically lesioning the NAc rhythm out increases weight gain inward rats (31).
Opiate signaling inward the CNS is a critical ingredient of hedonic processing. Researchers receive got long recognized the mightiness of opiates to increment feeding, together with the mightiness of blocking opiate signaling to decrease feeding (31, 32, 33). Opiate signaling inward the striatum (particularly the NAc) increases the palatability of food, together with this trial depends mostly on the mu opioid receptor subtype (34, 35). The mu opioid receptor blocker naloxone specifically decreases the palatability of nutrient together with the consumption of palatable nutrient inward rats together with humans, but has picayune impact on the intake of less palatable nutrient (36, 37, 38). Mice that lack the mu opioid receptor cistron are lean together with resistant to diet-induced obesity, suggesting that opioid-mediated nutrient palatability may hold out a major portion of the argue rodents teach obese on refined high-fat diets (39). Activating opioid signaling inward the striatum does non increment the amount a rodent volition piece of work for food, does non increment repast frequency, together with does non reinforce behavior, thus striatal opioids regulate hedonic processing (liking) without affecting vantage (wanting) (40).
It has been demonstrated many times inward the scientific literature together with inward my ain hands that rats volition consume a substantial amount of palatable nutrient fifty-fifty after they receive got already eaten less palatable nutrient to fullness (41). This is the "dessert effect"-- you've only finished a large repast together with you're stuffed, but you lot care to "make room" for unopen to other 200 calories when the cake rolls around. This seems to hold out related to opioid signaling, every bit the activation of this organisation inward the striatum increases both the liking of foods together with repast size (42).
Dopamine is critically involved inward vantage functions, together with it turns out to hold out a major regulator of nutrient intake together with torso fatness every bit well. Injecting dopamine into the encephalon reduces nutrient intake, together with the primary site of activeness appears to hold out inward the LH (43). Dopamine signaling inward the striatum regulates the motivation to obtain food, but non the enjoyment or consumption of nutrient that is readily accessible (44). Thus, inward the striatum it impacts motivation/reward (wanting) but non palatability (liking).
Drugs that activate sure dopamine receptors tin displace compulsive overeating of palatable foods together with weight gain (45). However, the dopamine organisation is complex, involving multiple receptor subtypes that receive got unlike functions inward unlike encephalon regions, together with unlike drugs touching these subtypes differently. The dopamine D2 receptor inward detail seems to hold out involved inward nutrient intake together with torso fatness. The D2 receptor activating drug bromocriptine causes obese loss inward a multifariousness of animate existence models of obesity, including humans inward unopen to studies (46). Obesity is associated amongst reduced D2 receptor density inward the striatum, together with at that topographic point is evidence that reduced striatal D2 receptors tin precede the evolution of obesity (47). There is also evidence inward rodents that chronic exposure to highly palatable nutrient tin cut down D2 receptor density inward the striatum (48), suggesting that exposure to hyperpalatable foods, inward improver to genetics (discussed below), tin atomic number 82 to an obesity-promoting pattern of D2 receptor aspect inward the brain. This is portion of a broader pattern of addiction-like changes that prepare inward the brains of animals chronically exposed to hyper-palatable/hyper-rewarding food.
If the effects of opioid together with dopamine signaling on palatability together with vantage really influence nutrient intake together with torso fatness, together with so drugs that impact these systems should hold out able to displace obese loss inward humans. Such a drug exists-- it's called Contrave, together with it is a combination of naltrexone (an opioid receptor blocker that acts mostly at mu together with kappa receptors) together with bupropion (dopamine-norepinephrine re-uptake inhibitor). Contrave has shown effectiveness every bit a obese loss drug inward humans, although side effects receive got prevented FDA approval (49). The proposed machinery of this drug is via the indirect activation of POMC cells inward the ARC, over again suggesting that reward/hedonic circuits influence those that regulate torso fatness.
One of the most interesting links betwixt reward/hedonic circuits together with hypothalamic circuits is via endocannabinoid signaling. It has been known for unopen to fourth dimension that marijuana increases the consumption of palatable foods together with causes weight gain if smoked oftentimes plenty (50). Today, nosotros know that endocannabinoid signaling is intimately involved inward hedonic together with vantage circuitry. Marijuana acts principally via the CB1 receptor (51). Mice lacking the CB1 receptor cistron CNR1 are lean together with resistant to diet-induced obesity (52). The CB1 receptor blocker Rimonabant is an effective obese loss drug inward humans, together with its trial appears to occur mostly if non solely inward the encephalon (53, 54). Rimonabant is basically "reverse marijuana". Perhaps non surprisingly, it was pulled from the marketplace yesteryear the FDA due to negative psychological side effects.
It is no coincidence that ii of the most effective obese loss drugs developed inward recent history, Contrave together with Rimonabant, both target vantage together with hedonic centers inward the brain.
6. Genetic differences that influence vantage and/or hedonic circuits should correlate amongst differences inward torso fatness
Each someone on this world carries a unique combination of cistron variants, together with inward unopen to cases these influence physical characteristics together with the reply to environmental factors. Some of these variants are inside dopamine receptor genes, together with thus receive got the potential to influence nutrient reward. Several studies receive got shown that polymorphisms of the D2 dopamine receptor associate amongst the opportunity of drug addiction, gambling addiction, together with obesity (55, 56, 57, 58, 59, 60). Polymorphisms inward other genes that influence dopamine signaling, including the D4 dopamine receptor, the dopamine re-uptake transporter, together with catechol-O-methyltransferase, receive got also been found to associate amongst obesity opportunity (61, 62, 63, 64).
Polymorphisms inward the CB1 cannabinoid receptor cistron CNR1 also associate amongst torso fatness (65, 66). This is consistent amongst the fact that the CB1 receptor knockout mouse is resistant to diet-induced obesity, together with the CB1 blocking drug Rimonabant reduces torso fatness inward humans (67).
I receive got non come upward across whatever reports of opioid receptor cistron polymorphism frequency inward obesity.
These findings back upward the hypothesis that vantage together with hedonic circuits inward the CNS influence torso fatness, together with that the pre-existing characteristics of these circuits tin explicate differences inward the reply to rewarding stimuli, together with differences inward torso fatness, inward the full general population.
7. On a cultural level, obesity prevalence should rail amongst changes inward the reward/palatability value of prevailing diet patterns
The evidence inward this category is the to the lowest degree good controlled, since many things receive got changed during the evolution of the "obesity epidemic". However, for the hypothesis to hold out convincing, at a minimum it has to hold out consistent amongst how diets inward most cultures receive got changed every bit obesity has increased inward recent years.
The obesity epidemic inward the U.S. has paralleled a pregnant shift inward nutrient culture. Here are a few examples to illustrate the trends (68). In the terminal 50 years:
- Fast nutrient spending increased from 2% to 18% of total nutrient spending
- Soda consumption increased yesteryear 250%
- Consumption of fresh potatoes decreased yesteryear 50%
- Consumption of processed potatoes (mostly fries together with chips) increased yesteryear 300%
- Between-meal snacks/drinks, specially processed snacks together with soda, receive got to a greater extent than than doubled (69)
Similar trends are apparent inward all affluent nations every bit the nutrient chain has teach increasingly commercialized together with gradually displaced traditional nutrient culture, together with invariably this has been accompanied yesteryear increased torso fatness on a population level.
That's non to enjoin that commercial nutrient is responsible for all obesity. Obesity has been documented for thousands of years, if non longer, including inward sure cultures that only had access to traditional ingredients (e.g., Polynesian islanders). However, inward these cases (including Europe earlier industrialization), obesity was mostly restricted to affluent individuals who benefited from skilled chefs together with alternative ingredients, every bit good every bit a sedentary lifestyle.
Some people receive got brought upward the examples of French Republic together with Republic of Republic of India every bit challenges to the nutrient vantage hypothesis, stating that both receive got a tradition of delicious food. That, of course, is true. However, it's of import to scream upward that most people traditionally didn't consume foie gras together with obese spiced curries every day, together with nutrient that you lot consume inward a eating theatre or every bit a tourist doesn't necessarily correspond peoples' day-to-day nutrient choices. In France, which I tin talk for because I spent a pregnant chunk of my life there, most meals are composed of relatively simple, fresh, home-cooked food. This is specially truthful for the older generations. The nutrient is non depression inward fat, or depression inward animate existence fat. It tastes good, but it isn't extravagant. Traditionally, people rarely ate at restaurants, which were expensive together with considered a special treat. As the nutrient organisation has industrialized, together with commercial nutrient has increasingly replaced habitation cooking, the prevalence of obesity has increased.
I'm non every bit familiar amongst traditional Indian food, together with I don't desire to pose every bit an practiced here, but I'm quite confident that what nosotros run into inward restaurants together with cookbooks inward the U.S. is non what the average Indian someone was eating 50 years ago, together with for the most portion silent non today. The traditional Indian diet, earlier industrialization, differed yesteryear part but was by together with large really depression inward obese together with relied heavily on plainly starch foods such every bit rice, millet together with wheat. This was supplemented amongst to a greater extent than exciting dishes based on legumes, vegetables, dairy together with occasionally meat. But my agreement is that, for an ordinary meal, these were pocket-size portions compared to the plainly starches that formed the backbone of the diet. I dubiousness the average Indian someone 50 years agone was making complex dishes using liberal quantities of ghee together with a dozen spices for dinner every night, or deep frying things. Spices together with ghee aren't gratis together with cooking similar that takes time, science together with special equipment-- is it a priority if you lot don't receive got much disposable income?
As Republic of Republic of India has industrialized, together with the diet has teach to a greater extent than diverse, to a greater extent than fatty, to a greater extent than refined together with to a greater extent than commercialized, obesity throughout the province has increased (particularly abdominal obesity), together with Republic of Republic of India at nowadays has a serious diabetes together with coronary view affliction occupation on its hands.
Conclusion
If you lot made it this far, you're a hero! As you lot receive got seen, a publish of mutually buttressing lines of evidence, including controlled diet studies, observational studies, neuroscience, pharmacology together with genetics, back upward the hypothesis that nutrient vantage together with palatability influence nutrient intake together with torso fatness. It's non every solar daytime that you lot come upward across an thought inward the diet-health literature that is consistently supported yesteryear so many independent lines of inquiry. This hypothesis isn't really sexy, which is i argue why it hasn't gained every bit much traction amongst earth every bit sure other ideas, but I'm non every bit good concerned nigh that. I only desire to empathize what causes obesity, together with this hypothesis has a lot of explanatory power.
The grade to which nutrient vantage together with palatability receive got driven the modern obesity epidemic remains opened upward to interpretation. However, inward 2011, the evidence has accumulated to the dot where it is clear that they play a role. I side amongst modern nutrient vantage researchers inward thinking it is a major factor, although at that topographic point are for certain others.
