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Controlling caloric intake and energy expenditure

May not be enough to keep weight stable

16 September, 2013

Whenever one talks about the need to keep optimal weight in order to reduce cardiovascular risk and other health hazards, one will always quote the mantra – eat healthy and stay fit, which means keeping the desired balance between caloric intake and energy expenditure. The standard equation says that 7000 kcal equal 1 kg of fat, so, if the energy balance over a period of time points is (-)7000 kcal, this negative figure should also be expressed while standing on the scale, which should show 1 kg reduction in weight. All guidelines and recommendations are based on this formulation, and the scenario of failure to maintain or reduce weight despite keeping the instructions is attributed solely to poor adherence to the intervention program. Now it seems that there may be other explanations. A study published recently in Science examined mice that were put in a system that could accurately measure both their caloric intake and energy expenditure [1]. Two groups were compared: normal mice and those with deletion of melanocortin 2 receptor accessory protein 2 (MRAP2), which are known to develop severe obesity at a young age. Even when fed the same amount of chow, null mice gained more weight than did wild-type mice. Only when the amount of food intake in null mice was further restricted to 10% (females) and 13% (males) less than that of wild-type mice was there equivalent weight gain. This was the case while mice were young but, at later stages of their life, the null mice demonstrated overt hyperphagia and associated weight gain.


The melanocortin receptor (MCR) family consists of five G-protein-coupled receptors (MC1R–MC5R) with diverse physiological roles [2]. They mediate signaling in response to adrenocorticotropic hormone (ACTH), and α-melanocyte-stimulating hormone (αMSH) and their competitive antagonists, agouti and agouti-related protein. The activity of the MCR subtypes is as follows: MC1R controls pigmentation, MC2R is a critical component of the hypothalamic–pituitary–adrenal axis, MC3R and MC4R have a vital role in energy homeostasis, and MC5R is involved in exocrine function. The melanocortin receptor accessory protein (MRAP) and its paralogue MRAP2 are small single-pass transmembrane proteins that have been shown to regulate MCR expression and function. In the adrenal gland, MRAP is an essential accessory factor for the functional expression of the MC2R/ACTH receptor. MC2R is also expressed in adipose tissue together with MC5R, where they mediate the potent lipolytic effects of ACTH and α-MSH. At the same time, there is evidence that signaling mediated by MC2R and MC5R in adipocytes inhibits production of leptin, indicating that possibly there is a control mechanism for modulation of adipose tissue function via a melanocortin–leptin axis. Loss of either MC2R or MRAP in humans causes severe resistance to ACTH, with resulting glucocorticoid deficiency. All mammals have a paralogous gene, MRAP2, which is predominantly expressed in the brain, most prominently in the pons and cerebellum but also in regions involved in energy homeostasis, such as the hypothalamus and brainstem. MRAP2 interacts with MC3R, which is involved in body weight and energy metabolism regulation. In knockout mice lacking the MC3R gene, nutrients are preferentially partitioned into fat at the expense of lean mass [3]. Importantly, increased feed efficiency, not hyperphagia, causes weight increase in these mice.

To investigate whether alterations in MRAP2 are associated with human obesity, obese and control individuals were studied for potential relevant mutations [1]. Only few rare variants were found in the obese cohorts, indicating that, if MRAP2 mutations contribute to severe human obesity, they do so rarely. Perhaps this is a relief, but in my mind the study opens a new angle in understanding overweight since other, yet unidentified genetic aberrations may be involved in abnormal handling of energy and ensuing weight gain. In conclusion, it was found that global or brain-specific inactivation of MRAP2 causes obesity in mice and that rare heterozygous variants in MRAP2 are associated with early-onset, severe obesity in humans. The mechanisms by which MRAP2 exerts its effects on body weight regulation remain to be firmly established but are likely to involve altered signaling through the various MCRs.

Amos Pines
Department of Medicine ‘T’, Ichilov Hospital, Tel-Aviv, Israel


1. Asai M, Ramachandrappa S, Joachim M, et al. Loss of function of the melanocortin 2 receptor accessory protein 2 is associated with mammalian obesity. Science 2013;341:275-8.
2. Novoselova TV, Jackson D, Campbell DC, Clark AJ, Chan LF. Melanocortin receptor accessory proteins in adrenal gland physiology and beyond. J Endocrinol 2013;217:R1-11.
3. Chen AS, Marsh DJ, Trumbauer ME, et al. Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass. Nat Genet 2000;26:97–102.

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