But why lack of sleep -- in particular the early, deep phase called non-REM sleep -- lowers levels of growth hormone has been a mystery.

In a study published in the current issue of the journal Cell, researchers from University of California, Berkeley, dissect the brain circuits that control growth hormone release during sleep and report a novel feedback mechanism in the brain that keeps growth hormone levels finely balanced.

The findings provide a map for understanding how sleep and hormone regulation interact. The new feedback mechanism could open avenues for treating people with sleep disorders tied to metabolic conditions like diabetes, as well as degenerative diseases like Parkinson's and Alzheimer's.

"People know that growth hormone release is tightly related to sleep, but only through drawing blood and checking growth hormone levels during sleep," said study first author Xinlu Ding, a postdoctoral fellow in UC Berkeley's Department of Neuroscience and the Helen Wills Neuroscience Institute. "We're actually directly recording neural activity in mice to see what's going on. We are providing a basic circuit to work on in the future to develop different treatments."

Because growth hormone regulates glucose and fat metabolism, insufficient sleep can also worsen risks for obesity, diabetes and cardiovascular disease.

The sleep-wake cycle

The neurons that orchestrate growth hormone release during the sleep-wake cycle -- growth hormone releasing hormone (GHRH) neurons and two types of somatostatin neurons -- are buried deep in the hypothalamus, an ancient brain hub conserved in all mammals. Once released, growth hormone increases the activity of neurons in the locus coeruleus, an area in the brainstem involved in arousal, attention, cognition and novelty seeking. Dysregulation of locus coeruleus neurons is implicated in numerous psychiatric and neurological disorders.

"Understanding the neural circuit for growth hormone release could eventually point toward new hormonal therapies to improve sleep quality or restore normal growth hormone balance," said Daniel Silverman, a UC Berkeley postdoctoral fellow and study co-author. "There are some experimental gene therapies where you target a specific cell type. This circuit could be a novel handle to try to dial back the excitability of the locus coeruleus, which hasn't been talked about before."

The researchers, working in the lab of Yang Dan, a professor of neuroscience and of molecular and cell biology, explored the neuroendocrine circuit by inserting electrodes in the brains of mice and measuring changes in activity after stimulating neurons in the hypothalamus with light. Mice sleep for short periods -- several minutes at a time -- throughout the day and night, providing many opportunities to study growth hormone changes during sleep-wake cycles.

Using state-of-the-art circuit tracing, the team found that the two small-peptide hormones that control the release of growth hormone in the brain -- GHRH, which promotes release, and somatostatin, which inhibits release -- operate differently during REM and non-REM sleep. Somatostatin and GHRH surge during REM sleep to boost growth hormone, but somatostatin decreases and GHRH increases only moderately during non-REM sleep to boost growth hormone.

Released growth hormone regulates locus coeruleus activity, as a feedback mechanism to help create a homeostatic yin-yang effect. During sleep, growth hormone slowly accumulates to stimulate the locus coeruleus and promote wakefulness, the new study found. But when the locus coeruleus becomes overexcited, it paradoxically promotes sleepiness, as Silverman showed in a study published earlier this year.

"This suggests that sleep and growth hormone form a tightly balanced system: Too little sleep reduces growth hormone release, and too much growth hormone can in turn push the brain toward wakefulness," Silverman said. "Sleep drives growth hormone release, and growth hormone feeds back to regulate wakefulness, and this balance is essential for growth, repair and metabolic health."

Because growth hormone acts in part through the locus coeruleus, which governs overall brain arousal during wakefulness, a proper balance could have a broader impact on attention and thinking.

"Growth hormone not only helps you build your muscle and bones and reduce your fat tissue, but may also have cognitive benefits, promoting your overall arousal level when you wake up," Ding said.

The work was funded by the Howard Hughes Medical Institute (HHMI), which until this year supported Dan as an HHMI investigator, and the Pivotal Life Sciences Chancellor's Chair fund. Dan is the Pivotal Life Sciences Chancellor's Chair in Neuroscience. Other co-authors of the paper are Peng Zhong, Bing Li, Chenyan Ma, Lihui Lu, Grace Jiang, Zhe Zhang, Xiaolin Huang, Xun Tu and Zhiyu Melissa Tian of UC Berkeley; and Fuu-Jiun Hwang and Jun Ding of Stanford University.

"If this receptor is impaired by genetic changes, mice show signs of loss of bone density at an early age - similar to osteoporosis in humans. Using the substance AP503, which was only recently identified via a computer-assisted screen as a stimulator of GPR133, we were able to significantly increase bone strength in both healthy and osteoporotic mice," explains Professor Ines Liebscher, lead investigator of the study from the Rudolf Schönheimer Institute of Biochemistry at the Faculty of Medicine.

In bone tissue, GPR133 is activated through the interaction of neighboring bone cells and mechanical strain. This triggers a signal that stimulates bone-forming cells (osteoblasts) and inhibits bone-resorbing cells (osteoclasts). The result: stronger, more resilient bones. The new active substance AP503 can mimic this natural activation. In the future, it could be used both to further strengthen healthy bones and to rebuild weakened ones - for instance, in cases of osteoporosis in women going through menopause.

Great potential for an aging population

In an earlier study, researchers at Leipzig University had already found that activation with AP503 also strengthens skeletal muscle. "The newly demonstrated parallel strengthening of bone once again highlights the great potential this receptor holds for medical applications in an aging population," says Dr Juliane Lehmann, lead author of the study and a researcher at the Rudolf Schönheimer Institute of Biochemistry. The Leipzig research team is already working on several follow-up projects to explore the use of AP503 in various diseases and to further investigate the role of GPR133 in the body.

Background

For more than ten years, the study of adhesion G protein-coupled receptors has been a key focus at Leipzig University within Collaborative Research Centre 1423, Structural Dynamics of GPCR Activation and Signaling. Internationally, Leipzig is regarded as a leading center in this field of research.

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In a new study, which is published in PNAS, experts discovered that older people produce a glycosylated protein called apoplipoprotein D (ApoD), which is involved in lipid metabolism and inflammation, at much higher levels than in younger people. This has the effect of reducing the patient's ability to resist virus infection, resulting in a more serious disease outcome.

The team established that highly elevated ApoD production with age in the lung drives extensive tissue damage during infection to reduce the protective antiviral type I interferon response.

The research was an international collaboration led by scientists from the China Agricultural University, University of Notttingham, Institute of Microbiology (Chinese Academy of Sciences), National Institute for Viral Disease Control and Prevention (Chinese Centre for Disease Control and Prevention) and the University of Edinburgh.

"Aging is a leading risk factor in influenza-related deaths. Furthermore, the global population is aging at an unprecedented rate in human history, posing major issues for healthcare and the economy. So we need to find out why older patients often suffer more severely from influenza virus infection," says Professor Kin-Chow Chang from the School of Veterinary Medicine and Science at the University of Nottingham, and co-author on the paper.

In this new study, the team investigated the mechanisms behind increased severity of influenza virus infection with age using an aging-mouse model and appropriate donor human tissue sections.

They identified ApoD as an age-related cell factor that impairs the activation of the immune system's antiviral response to influenza virus infection by causing extensive breakdown of mitochondria (mitophagy) resulting in greater production of virus and lung damage during infection. Mitochondria are essential for cellular production of energy and for induction of protective interferons.

ApoD is therefore a target for therapeutic intervention to protect against severe influenza virus infection in the elderly which would have a major impact on reducing morbidity and mortality in the aging population.

Professor Chang, added: "There is now an exciting opportunity to therapeutically ameliorate disease severity of the elderly from influenza virus infection by the inhibitory targeting of ApoD."

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