Melanocortin-4 Receptor Signaling Is Required for Weight Loss after Gastric Bypass Surgery

Hatoum, Ida J.; Stylopoulos, Nicholas; Vanhoose, Amanda M.; Boyd, Kelli L.; Yin, Deng Ping; Ellacott, Kate L. J.; Li, Lian; Blaszczyk, Kasia; Keogh, Julia M.; Cone, Roger D.; Farooqi, I. Sadaf; Kaplan, Lee M.

doi:10.1210/jc.2011-3432

Cited by 144 publications

(118 citation statements)

References 37 publications

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“…Given the role of the central MC4R system in the control of energy balance (5) and pathophysiology of human obesity (119), (120). These studies suggest either that non-MC4R-mediated mechanisms by which RYGBP affects energy balance are not powerful enough to overcome complete absence of MC4R signaling or that the MC4R system is intrinsic to the biological response to RYGBP ( Figure 2).…”

Section: Role Of the Mc4r Pathwaymentioning

confidence: 99%

Roux-en-Y gastric bypass: effects on feeding behavior and underlying mechanisms

Manning¹,

Pucci²,

Batterham³

2015

J. Clin. Invest.

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Section: Role Of the Mc4r Pathwaymentioning

confidence: 99%

Roux-en-Y gastric bypass: effects on feeding behavior and underlying mechanisms

Manning¹,

Pucci²,

Batterham³

2015

J. Clin. Invest.

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“…Most of the recent animal studies and some studies in humans have examined the role of the melanocortin system, which seems to be central to many peripheral and brain-derived stimuli that control eating and body weight (55,92,93,157). In humans, the sufficiency of one functional MC4r gene for effective RYGB outcome was indicated in some studies, including RYGB or VSG-operated humans (157).…”

Section: Cns Eating and Body Weight Controls After Rygbmentioning

confidence: 99%

The physiology underlying Roux-en-Y gastric bypass: a status report

Lutz

Bueter

2014

American Journal of Physiology-Regulatory, Integrative and Comp

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Lutz TA, Bueter M. The physiology underlying Roux-en-Y gastric bypass: a status report. Am J Physiol Regul Integr Comp Physiol 307: R1275-R1291, 2014. First published September 24, 2014 doi:10.1152/ajpregu.00185.2014.-Obesity and its related comorbidities can be detrimental for the affected individual and challenge public health systems worldwide. Currently, the only available treatment options leading to clinically significant and maintained body weight loss and reduction in obesity-related morbidity and mortality are based on surgical interventions. This review will focus on two main clinical effects of Roux-en-Y gastric bypass (RYGB), namely body weight loss and change in eating behavior. Animal experiments designed to understand the underlying physiological mechanisms of these post-gastric bypass effects will be discussed. Where appropriate, reference will also be made to vertical sleeve gastrectomy. While caloric malabsorption and mechanical restriction seem not to be major factors in this respect, alterations in gut hormone levels are invariably found after RYGB. However, their causal role in RYGB effects on eating and body weight has recently been challenged. Other potential factors contributing to the RYGB effects include increased bile acid concentrations and an altered composition of gut microbiota. RYGB is further associated with remarkable changes in preference for different dietary components, such as a decrease in the preference for high fat or sugar. It needs to be noted, however, that in many cases, the question about the necessity of these alterations for the success of bariatric surgery procedures remains unanswered.Roux-en-Y gastric bypass; vertical sleeve gastrectomy; gut hormones; restriction; malabsorption; energy expenditure THE OBESITY EPIDEMIC AND ITS related comorbidities constitute a major challenge for both personal health and public health systems worldwide. The enormous increase in knowledge about the physiological mechanisms that control eating and body weight contrasts with the lack of available pharmacological therapies leading to safe, efficient, and long-lasting body weight reductions and amelioration of obesity-related comorbidities. However, recent insights into underlying mechanisms of obesity and bariatric surgery have led to promising perspectives in respect to gut hormone-based strategies against obesity. Nevertheless, best results for maintained weight reduction and improvement of comorbidities are still achieved by surgical means (22,88,121,135,136). This review aims to summarize key findings in respect to underlying physiological mechanisms of the Roux-en-Y gastric bypass (RYGB) procedure, which is the most commonly performed bariatric operation worldwide and thus, by many is considered as the gold standard in bariatric surgery. Sporadic reference will also be made to vertical sleeve gastrectomy (VSG) when appropriate. Both operations reduce eating at least temporarily (19,140,143) and lead to changes in food preferences (20,27,72). The majority of data collected with...

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“…With the exception of a few rare variants, 35 all studies looking at patients with MC4R variants found that gastric bypass surgery was fully effective. 14,33,35,36 However, gastric banding in one rare patient with complete loss of MC4R functionality did not produce a lasting reduction in body weight.…”

Section: Potential Underlying Mechanisms For Change In Set Pointmentioning

confidence: 89%

“…14 Another study concluded that complete absence of MC4R signaling in homozygous, but not in heterozygous knockout mice, abrogated the effectiveness of RYGB. 33 Interpretation of that study is made difficult due to high mortality, low number of animals and the unusually low weight gain in MC4R-deficient mice, which was less than observed in other studies using homozygous MC4R-deficient mice. 34 Using chronic pharmacological blockade of brain MC4R signaling 3-4 months after RYGB or sham surgery in rats (see Discussion above and Figure 1), we concluded that brain MC4R signaling is not the critical mechanism by which RYGB lowers defended body weight level.…”

Section: Potential Underlying Mechanisms For Change In Set Pointmentioning

confidence: 91%

Does gastric bypass surgery change body weight set point?

et al. 2016

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The relatively stable body weight during adulthood is attributed to a homeostatic regulatory mechanism residing in the brain which uses feedback from the body to control energy intake and expenditure. This mechanism guarantees that if perturbed up or down by design, body weight will return to pre-perturbation levels, defined as the defended level or set point. The fact that weight re-gain is common after dieting suggests that obese subjects defend a higher level of body weight. Thus, the set point for body weight is flexible and likely determined by the complex interaction of genetic, epigenetic and environmental factors. Unlike dieting, bariatric surgery does a much better job in producing sustained suppression of food intake and body weight, and an intensive search for the underlying mechanisms has started. Although one explanation for this lasting effect of particularly Roux-en-Y gastric bypass surgery (RYGB) is simple physical restriction due to the invasive surgery, a more exciting explanation is that the surgery physiologically reprograms the body weight defense mechanism. In this non-systematic review, we present behavioral evidence from our own and other studies that defended body weight is lowered after RYGB and sleeve gastrectomy. After these surgeries, rodents return to their preferred lower body weight if over-or underfed for a period of time, and the ability to drastically increase food intake during the anabolic phase strongly argues against the physical restriction hypothesis. However, the underlying mechanisms remain obscure. Although the mechanism involves central leptin and melanocortin signaling pathways, other peripheral signals such as gut hormones and their neural effector pathways likely contribute. Future research using both targeted and non-targeted 'omics' techniques in both humans and rodents as well as modern, genetically targeted, neuronal manipulation techniques in rodents will be necessary.

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Melanocortin-4 Receptor Signaling Is Required for Weight Loss after Gastric Bypass Surgery

Cited by 144 publications

References 37 publications

Roux-en-Y gastric bypass: effects on feeding behavior and underlying mechanisms

Roux-en-Y gastric bypass: effects on feeding behavior and underlying mechanisms

The physiology underlying Roux-en-Y gastric bypass: a status report

Does gastric bypass surgery change body weight set point?

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