Researchers Link Orexin-A to Weight Gain and Cardiometabolic Risk After Menopause

Menopause is marked by a decline in estrogen and the cessation of ovarian function. During this transition, many women experience increases in body weight and fat mass, although researchers continue to debate whether these changes are caused directly by falling estrogen levels or by a combination of aging, reduced physical activity and metabolic shifts.

Studies of hormone-replacement therapy have produced mixed findings. Some investigations found little effect on body mass index, fat mass or fat-free mass, while others reported that hormone therapy may reduce weight gain or limit the shift from gynoid to android fat distribution. Other reports suggested that oral estrogen could increase body fat by reducing lipid oxidation.

Experts note that estrogen may influence body composition through several mechanisms. These include effects on adipose tissue lipoprotein lipase, appetite regulation, physical activity and resting energy expenditure. Resting energy expenditure normally declines with age, but evidence suggests that the decrease may accelerate during the menopausal transition.

A reduction in resting energy expenditure may promote fat mass gain, which can contribute to obesity-related conditions such as worsening cardiovascular risk and type 2 diabetes. Estrogen depletion itself has also been associated with higher cardiovascular risk, including increased blood pressure and adverse changes in cholesterol and triglyceride levels.

Orexin-A, also known as hypocretin-1, is a hypothalamic neuropeptide involved in feeding behaviour, sleep-wake regulation, energy balance and neuroendocrine activity. Although orexin was first studied for its central nervous system effects, researchers have also identified orexin receptors in peripheral tissues, including the gastrointestinal tract, pancreas, adrenal glands and adipose tissue.

Research cited in the article found that postmenopausal women not receiving hormone-replacement therapy had higher plasma orexin-A levels than women receiving therapy and women of reproductive age. The same findings linked higher orexin-A levels with cardiovascular risk factors, including blood glucose, lipid profile, blood pressure and body mass index.

Scientists believe the relationship between estrogen and orexin-A may reflect the close connection between energy balance and reproductive function. Orexin-A appears to interact with the hypothalamic-pituitary-gonadal axis, and experimental studies suggest that sex steroids and orexin signalling may regulate one another.

Orexin-A may also influence sympathetic nervous system activity, heart rate, blood pressure, thermogenesis and metabolic rate. These actions could help explain why changes in orexin signalling may be relevant to postmenopausal cardiovascular morbidity and mortality.

The article also noted the clinical importance of orexin pathways in sleep regulation. Orexin deficiency has been linked to narcolepsy, while orexin receptor antagonists such as suvorexant have shown benefit in improving sleep efficiency in patients with primary insomnia.

Researchers concluded that a deeper understanding of orexin-A may provide new insight into menopause-related symptoms, including appetite changes, weight gain, vasomotor symptoms, sleep disturbance and cardiovascular risk. They also suggested that future studies should examine orexin pathways in reproductive abnormalities and metabolic conditions involving altered resting energy expenditure.

Source: Hindawi Publishing Corporation Obstetrics and Gynecology International. Volume2013,ArticleID209812. http://dx.doi.org/10.1155/2013/209812