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Glucotanycytes: a role for hypothalamic barriers in the control of metabolism by peripheral glucose

Periodic Reporting for period 1 - GLUCOTANYCYTES (Glucotanycytes: a role for hypothalamic barriers in the control of metabolism by peripheral glucose)

Reporting period: 2017-12-01 to 2019-11-30

"The escalating epidemic of obesity, type-2 diabetes (T2D) and metabolic syndrome represents one of the most pressing and costly biomedical challenges confronting modern society. The impaired action of peripheral hormones like leptin, insulin and incretins on brain circuits controlling feeding and energy homeostasis (also known as ""central hormone resistance""), is increasingly recognized as playing a role in the pathophysiology of these disorders. Those hormones transmit information about the energy status of peripheral tissues, such as pancreas, liver, white and brown adipose tissue and gastrointestinal track.

These hormones reach their central brain targets by crossing the blood-brain barrier
at the level of microvessels or at circumventricular organs (CVOs) such as the median eminence, situated adjacent to the arcuate nucleus of the hypothalamus.

Appetite, energy balance, glucose and lipid metabolism are all partially controlled by select neurons located in the arcuate nucleus of the hypothalamus (ARH). However, much remains to be uncovered concerning the physiological mechanisms that control the access of blood-borne metabolic factors such as glucose and peripheral hormones to ARH neuronal circuits.

The laboratory where this project has been conducted (Development and Plasticity of the Neuroendocrine Brain, INSERM U1172, Lille, France) has raised the groundbreaking notion that tanycytes from the median eminence, a specific type of hypothalamic glial cells, act as ""gatekeepers"" that regulate the access of blood-borne signals to the hypothalamus, and in particular, their vesicular transport into the cerebrospinal fluid, from where they enter metabolic-hormone-sensitive regions.
The overall objective of the GLUCOTANYCYTES project is to elucidate the function of hypothalamic tanycytic barriers in the control of energy homeostasis with respect to glucose metabolism and peripheral hormone access to the hypothalamus."
The control of body weight and glucose homeostasis are the main target for T2D treatment. Therapies based on co-administration of the incretin glucagon-like peptide-1 (GLP-1) long-acting analogues and insulin are becoming popular in the treatment of T2D in order to modulate both glycemia and insulin resistance. Actually, GLP-1 and its agonists enhance glucose-induce insulin secretion and contribute to body weight loss through their brain action in the hypothalamus, modulating food intake and nutritional partitioning.

Liraglutide, an agonist of the glucagon-like peptide-1 (GLP1) receptor, has been recently approved for the treatment of obesity in individuals with and without T2D and is now also being considered for the treatment of non-alcoholic fatty liver disease. Despite its beneficial effects on metabolism, it is still unclear whether liraglutide acts through specialized cells in the brain or via a direct effect on pancreatic beta cells.

Specifically, we hypothesized that tanycytes mediate the entry of liraglutide into the brain where it modulates its metabolic effects. We also conjectured that once in the brain, liraglutide is involved in the regulation of insulin secretion.
Herein, we demonstrate that access of liraglutide to hypothalamic neurons is provided by tanycytes rather than crossing of the blood-brain vessels, importantly, the blockade of vesicular trafficking in tanycytes blunted liraglutide-mediated acute neuronal activation in the in the hypothalamus and its metabolic effects, including insulin secretion after an oral glucose challenge.
Liraglutide enters the brain by transcytosis through hypothalamic tanycytes to induce satiety and weight loss. Unexpectedly, we also demonstrate that liraglutide-induced insulin secretion is regulated by the central nervous system.
Our results suggest that tanycytes are master regulator of the body's energy/metabolic status. A major question is how the plasticity of the tanycytic barrier, modulated by energy status and maybe altered by glucotoxicity, impacts the action of liraglutide treatment in patients with metabolic disorder such as obesity, non-alcoholic-fatty-liver-disease and T2D, may serve as therapeutic target to treat these conditions.
The understanding of how liraglutide reaches the hypothalamus thought tanycytes, and if the energy status by itself can modulate the access of it to the brain, would provide crucial information of how central drugs should be administered. This knowledge will provide a new approach of metabolic syndrome and T2D treatment, in which the energy homeostasis of the patient should be considered in order to modulate the posology. In addition, is vital relevance the understanding how liraglutide analogues centrally modulates insulin secretion, giving mire information of how different T2D medicaments should be combined whit other drugs.
Tanycytic transport of liraglutide mediates its anti obesity effects