POMC Deficiency With High Adiponectin Levels and Obesity Seen in Mouse Study
In contrast to previous reports, POMC deficiency leads to both obesity and high levels of the protein adiponectin, a study in mice suggested.
Shedding light on the molecular workings of POMC deficiency, a rare form of genetic obesity, the research shows that a previously unknown pathway drives the regulation of blood adiponectin levels by nerve cells containing the POMC protein.
The study, “Hypothalamic POMC deficiency increases circulating adiponectin despite obesity,” was published in the journal Molecular Metabolism.
Neurons of the melanocortin system in a brain area called the hypothalamus play a central role in regulating one’s satiety, or feeling full, as well as glucose (sugar) homeostasis, and energy expenditure.
Impaired expression of the POMC gene in these nerve cells or alterations in the melanocortin 4 receptor (MC4R) cause insatiable hunger, or hyperphagia, and low energy expenditure, ultimately resulting in obesity.
Researchers at University of Michigan Medical School measured blood levels of adiponectin in mice lacking the POMC gene in an area of the hypothalamus.
Compared to control (unaffected) animals, adiponectin levels and body weight were significantly higher in male and female mice with no POMC at 9 weeks of age (young adults). Female mice, but not males, continued to show elevated adiponectin levels despite chronic calorie restriction from 16 weeks of age. This finding contrasted with previous results linking obesity with low adiponectin levels.
Using a combination of genetic engineering with injection of a compound called tamoxifen, the team then restored POMC expression in the hypothalamus of the mice. (Tamoxifen is used to prevent and treat breast cancer.)
This approach lowered adiponectin levels to control values, but could not fully normalize body weight or the amount of fat mass. Similar decreases in adiponectin were seen with acute treatment with melanotan II, a form of the alpha-melanocyte-stimulating hormone.
As part of the melanocortin system, POMC regulates hunger through MC4R. In line with previous studies, the team found that altering melanocortin signaling in the brain influenced adiponectin levels in the blood. However, this link was not due to a direct effect on adipocytes (fat cells), but rather via reducing the activity of sympathetic nerves, which affect many organ systems and redirect oxygen-rich blood to areas needed during intense physical demand.
In agreement, mice lacking POMC were less able to regulate body temperature and to lower levels of adrenaline and norepinephrine in fat pads than controls animals, which indicates reduced sympathetic activity. Injecting noradrenaline into female mice lacking POMC lowered adiponectin levels.
“In summary, to the best of our knowledge, this study provides the first evidence that despite obesity, the [mouse model lacking POMC expression] has high circulating adiponectin levels, which demonstrated that increased fat mass is not necessarily correlated with hypoadiponectinemia [low adiponectin levels],” the researchers wrote.
“Our study demonstrated that it is possible to alter adiponectin levels in vivo [in a living body] by modifying sympathetic outflow, thus providing a possible explanation for our clinical observations,” they added.
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