Gut–brain axis underpins the metabolic syndrome
MedWire News: A neural circuit in the brain directly regulates cholesterol metabolism in the liver, indicate results from an animal study.
Their study, which appears in Nature Neuroscience, suggests that melanocortin signaling may be a promising target for the treatment of hypercholesterolemia and the metabolic syndrome.
Matthias Tschöp (University of Cincinnati, Ohio, USA) and colleagues hypothesized that a gut–brain axis integrates all the physiologic components known to be affected in the metabolic syndrome. This axis, they propose, “in addition to regulating glucose homeostasis, blood pressure, food intake, and body weight, also likely controls cholesterol metabolism.”
To investigate, they administered the gut hormone ghrelin to wild-type mice, daily for 1 week. This not only increased body fat, but also significantly increased total plasma cholesterol levels, whereas triglycerides and plasma glucose were unchanged.
As most of ghrelin’s metabolic effects are believed to be mediated via its primary target in the central nervous system (CNS), the hypothalamic melanocortin system, the team then manipulated this CNS circuit.
Inhibition of melanocortin signalling, either directly or indirectly, led to increased circulating levels of total and high-density lipoprotein (HDL) cholesterol. Conversely, activating this pathway using the satiating gut hormone glucagon-like peptide-1 decreased total and HDL cholesterol levels.
“These data indicate that circulating cholesterol levels can be both positively and negatively regulated in response to the action of peripheral gastrointestinal hormones,” write Tschöp et al.
In subsequent experiments, the team showed that the neuroendocrine cholesterol regulation is “physiologically relevant” and that the hypothalamic melanocortin receptor MCR-4 is “crucial” for the neuroendocrine control of HDL cholesterol.
They also demonstrated that this “gut–brain control system” regulates cholesterol metabolism in response to changes in gastrointestinal nutrient availability, and that HDL cholesterol levels were increased in rats prone to diet-induced obesity.
Importantly, they found that CNS control of hepatic cholesterol synthesis could not fully explain the “powerful” neuroendocrine control of circulating HDL cholesterol, and suggest that “acute CNS signalling changes can potently decrease plasma cholesterol without changing body fat mass.”
The researchers note that numerous synthetic agonists for hypothalamic melanocortin receptors have been described, and that potent ghrelin receptor antagonists are currently in development.
“Direct or indirect pharmacological modulation of hypothalamic melanocortin tone may offer a potent way to treat hypercholesterolemia and to simultaneously target all major components of the metabolic syndrome,” they conclude.
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By Joanna Lyford