{"id":294433,"date":"2019-07-16T15:13:59","date_gmt":"2019-07-16T18:13:59","guid":{"rendered":"https:\/\/revistapesquisa.fapesp.br\/?p=294433"},"modified":"2020-02-05T18:23:45","modified_gmt":"2020-02-05T21:23:45","slug":"an-enemy-unknown","status":"publish","type":"post","link":"https:\/\/revistapesquisa.fapesp.br\/en\/an-enemy-unknown\/","title":{"rendered":"An enemy unknown"},"content":{"rendered":"
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Allen Mouse Brain Atlas<\/span><\/a> Under food deprivation, growth hormone activates hunger neurons (red dots in the image above<\/em>)Allen Mouse Brain Atlas<\/span><\/p><\/div>\n

Anyone who has ever dieted knows the process. After taking the plunge and starting on a diet, the digits on the scale will normally begin to drop whatever the strategy. But the pace of weight loss soon begins to slow, even with the aid of medication, eventually stalling altogether or, even worse, reverse into weight gain. The way humans\u2019 and other species\u2019 organisms have been shaped by evolution can partly explain why losing weight is difficult. Thousands of years of food being in short supply and requiring substantial effort to be gotten have endowed our bodies with powerful and complex strategies for conserving energy. In experiments on mice, a research group led by physiologist Jos\u00e9 Donato Junior, of the University of S\u00e3o Paulo\u2019s Institute of Biomedical Sciences (ICB-USP), has found yet another mechanism acting against weight loss.<\/p>\n

The culprit is a compound known for a century but hitherto unsuspected of: growth hormone, a protein produced by the pituitary\u2014a gland at the base of the brain\u2014that acts on peripheral tissues. Growth hormone is secreted maximally during sleep. It increases calorie expenditure, releases energy stored in adipose tissue, and induces cell growth and cell repair in bones, muscles, and the gut. Now, the USP team has found that when food intake is diminished, growth hormone activates a region of the brain that induces hunger and reduces energy expenditure. As a result, it becomes more difficult to lose weight.<\/p>\n

Donato and his colleagues presented evidence of this previously unnoticed effect\u2014observed in experiments in mice\u2014in a paper published in the February 8 edition of Nature Communications<\/em>. \u201cWhen calorie intake is restricted, the level of growth hormone rises and our bodies go into survival mode: instead of modulating growth, it signals the need for food intake and to conserve energy,\u201d explains Donato.<\/p>\n

The finding came as somewhat of a surprise to experts in the field. \u201cWe often find new functions for known hormones, but none as significant as this,\u201d says endocrinologist L\u00edcio Velloso of the University of Campinas (UNICAMP), an expert in biochemical mechanisms associated with obesity and diabetes. \u201cIt has never been so clearly demonstrated that growth hormone acts on the brain to regulate hunger and energy expenditure.\u201d<\/p>\n

Fasting has been known to increase the release of growth hormone since the 1960s. In trials with healthy volunteers at a hospital in New York, physician Solomon Berson (1918\u20131972) and medical physicist Rosalyn Yalow (1921\u20132011) observed that prolonged food deprivation (two and a half days without eating) increased the release of growth hormone. They were oblivious, however, to the implications or the reasons for this occurring. \u201cIt appeared to be a paradoxical effect,\u201d Donato observes. \u201cWhy would a nutrient-deprived body channel its efforts to the energy-consuming process of growth?\u201d<\/p>\n\n \n \n \n <\/picture>Infographic<\/strong> Ana Paula Campos\u2002Ana Paula Campos (design), Freepik (illustration), Isadora Clivatti Furigo \/USP (image)<\/span>\n

The answer to this question came in the results published in February. To discover how hormones act on the central nervous system, Donato and his team decided to focus their research on the brain rather than on peripheral tissue as other researchers had done. \u201cThe action of growth hormone in hunger regulation has long remained elusive,\u201d says Brazilian biochemist Marcelo Dietrich of the Yale School of Medicine, who investigates the biochemical mechanisms that control hunger and satiety.<\/p>\n

The first step was to identify the site where growth hormone acts on the brain and its effect on hunger and energy consumption. In an initial test as part of her postdoctoral fellowship under Donato, physiologist Isadora Clivatti Furigo administered growth hormone marked with a substance that allows tracking to healthy rodents. She then examined the hypothalamus, a small region of the brain that controls body temperature, thirst, tiredness, sleep, and of course hunger. She noticed that the hormone bound to cells in at least 10 areas. One in particular caught her eye: the arcuate nucleus. This minute area contains a small group of cells (only a few thousand in mice) known to be involved in regulating food intake and energy expenditure. These neurons, known as hunger neurons, produce two compounds, a neuropeptide known as AgRP and the neuropeptide Y (NPY)\u2014which is why they are also called AgRP\/NPY neurons. These compounds act on other areas of the brain, causing the body to yearn for food.<\/p>\n

Triggering hunger<\/strong>
\nThe increased concentration of growth hormone in the hypothalamus had the effect of activating hunger neurons. One day after receiving a dose of the hormone, the treated rodents ate more than the mice that had received an innocuous solution (placebo). Animals in the first group also spent less energy than the placebo group, suggesting that high levels of growth hormone in the brain act as a trigger for hunger and energy savings. \u201cThis paper has opened up a whole new field of research,\u201d says endocrinologist Cesar Boguszewski, who heads the Neuroendocrinology Unit at the Federal University of Paran\u00e1\u2019s (UFPR) university hospital. \u201cIf this effect is observed in humans, it may help to understand why weight-loss diets often fail.\u201d<\/p>\n

To confirm that the increased hunger was due to the action of this hormone on AgRP\/NPY neurons, the researchers decided to make the mice unresponsive to growth hormone. Donato and Furigo received mice that had been genetically modified so that growth hormone receptors would not be present in the entire brain. The genetically modified mice were prepared by molecular biologist John Kopchick, of the University of Ohio, best known for developing a drug that inhibits growth hormone. At USP\u2019s Laboratory of Functional Neuroanatomy, the Brazilian duo used a genetic manipulation strategy called Cre-Lox recombination\u2014which precedes the now-more-popular CRISPR technology\u2014to cause the receptors to be absent only on hunger neurons.<\/p>\n\n \n \n \n <\/picture>Infographic<\/strong> Ana Paula Campos\u2002Ana Paula Campos (design), The Noun Project (illustration)<\/span>\n

When administered a standard laboratory diet, the mice without growth hormone receptors on the AgRP\/NPY neurons ate as much as their non-genetically modified counterparts. They also exhibited similar levels of activity, body weight and body composition (fat mass). But when their diet was restricted to 40% of their normal intake, the mice that had not been genetically modified began to move about less and decrease their energy expenditure. In contrast, the mice with hunger neurons without growth hormone receptors showed virtually no alteration in levels of activity. Consequently, this group lost 20% more weight\u2014primarily fat mass\u2014than the animals in the other group. \u201cWithout growth hormone receptor, AgRP\/NPY neurons appear to be oblivious to food deprivation,\u201d says Furigo.<\/p>\n

In the next phase, the researchers tested something closer to a possible weight-loss treatment for humans. They restricted food intake and gave the rodents two daily doses of pegvisomant, a drug used to treat people with acromegaly\u2014a condition in which the extremities grow abnormally large as a result of excessive growth hormone. In doing so they were attempting to maximize weight loss without genetic modification. With the rodents, it worked. The mice given pegvisomant shed more weight than those in the placebo group because they sustained high energy expenditure even when food-deprived. \u201cThis is a proof of concept that it may be possible to use this type of medication to help people achieve weight loss,\u201d suggests Donato. \u201cFor people on a diet, a treatment with this compound might make growth hormone levels go back to normal, reducing the sense of hunger while keeping energy expenditure high.\u201d<\/p>\n