Regulation of Glycemia by Central Nervous System (REGLYS)

Nutrients, particularly lipids, modulate the regulation of glucose homeostasis through their effects on the central nervous system, or “lipid sensing,” and lead to modifications in the neural control of insulin secretion and action, food intake behavior, and energy expenditure. We have highlighted the predominant role of an enzyme responsible for lipid hydrolysis, lipoprotein lipase, in cerebral lipid sensing (Laperrousaz et al., Front Endocrinol 2018; Laperrousaz et al., Diabetologia 2017; Picard et al., Molecular Metabolism 2013). We also contributed to revealing the role of the ACBP (Acyl-CoA binding protein) in the control of food intake and body weight following intravenous administration (Bravo-San Pedro et al., Cell Metab 2009), and we are now exploring the effects of this protein in the olfactory bulb of mice. We have also focused on the Elovl2 enzyme, a long-chain fatty acid elongase. We showed that this enzyme, specific for the endogenous synthesis of docosahexaenoic acid (DHA), was deregulated in vitro under conditions of glucolipotoxicity (when insulin secretion is also decreased), and that restoring its expression via a viral approach led to the restoration of insulin secretion (Bellini et al., Diabetologia 2018; Cruciani-Guglielmacci et al., Mol Metab 2017), through a reduction in ceramide accumulation. We then demonstrated that mice deficient in Serine Palmitoyl Transferase 2 in hepatocytes are protected against obesity induced by a high-fat diet, as well as the resulting glucose intolerance. The mechanisms involved include reduced intestinal lipid absorption due to disruption in bile acid composition, produced by the liver (Lallement et al., BBA lip 2023). In addition to animal models of obesity and type 2 diabetes, we have developed MASH (Metabolic-associated Steatohepatitis) models to test candidate molecules for the treatment of the disease. Finally, we are participating in a study on the role of intestinal gluconeogenesis in the behavioral reinforcement of anorexia. Our hypothesis is that glucose production in the portal vein, stimulated by caloric restriction, could facilitate adaptation to chronic energy deficiency through its effects on the central nervous system.

Inter-organ dialogue

In a fasting state, our sense of smell is highly sensitive to food odors, allowing us to appreciate what we eat. The first symptom in individuals suffering from olfactory loss (anosmia, hyposmia) is the loss of food enjoyment. In all mammals, the olfactory system not only detects and encodes olfactory information (especially food odors) but also regulates certain mechanisms of energy balance control. A neurometabolic pathway between the olfactory bulb and the pancreas, dependent on GLP-1 signaling, regulates insulin secretion and blood glucose levels (Montaner et al. 2024, Nature Communications).

We have demonstrated in mice the existence of a new neurometabolic axis between the olfactory bulb and the pancreas, which includes a hypothalamic relay via the LHA (lateral hypothalamic area) and the PVN (paraventricular nucleus) that controls both sympathetic and parasympathetic nervous systems (Montaner et al., 2023, Molecular Metabolism; Montaner et al., 2024, Nature Communications). We have shown that this axis is regulated by GLP-1 incretin signaling in the olfactory bulb, which opens the possibility of analyzing the central mechanisms induced by pharmacomimetics of this system, such as Ozempic® or Wegovy® (antidiabetic drugs that induce weight loss), whose brain actions remain poorly understood.

We use murine models of obesity induced by a high-calorie diet (Western Diet), which we compare to age-matched normoweight mice. We continue to study the GLP-1 / GLP-1 Receptor system using pharmacological or pharmacogenetic techniques, as well as its consequences on energy metabolism regulation and olfactory behavior. Finally, we are also studying the outcome of cerebrovascular activity in obese mice (Soleimanzad et al., in press, International Journal of Obesity).

Patient Associations
Hirac Gurden supports the associations “Anosmie.org” (developing an olfactory rehabilitation protocol for individuals suffering from olfactory disorders), “Culture et Hôpital” (creating an olfactory stimulation workshop in geriatrics, EHPAD), and the Miam-Miam group (olfactory goose game for children with oral intake disorders, Hôpital Debré, Paris).

Neurometabolic pathway between the olfactory bulb and the pancreas, dependent on GLP-1 signaling and regulating insulin levels and blood glucose (Montaner et al. 2024, Nature Communications).

The molecular mechanisms of metabolic disorders such as type 2 diabetes and obesity are found to be similar to those of neurodegenerative diseases like Alzheimer’s disease (AD). Therefore, we aim to understand the factors associated with cognitive deficits, diabetes, and obesity for targeted management and prevention strategies. The alteration of certain signaling pathways can be characterized by a brain/pancreas/adipose tissue axis linking beta cell and adipocyte dysfunction to cognitive impairments. We have demonstrated that the DYRK1A kinase is involved not only in deficits in neurogenesis, learning, and memory, but also in inflammation, glucose, and lipid metabolism. To further investigate the role of signaling pathways involving DYRK1A on the brain/pancreas/adipose tissue axis, we will rely on our previous findings demonstrating the positive effects of a molecule with neuroprotective and neurotrophic effects (patent pending) on DYRK1A expression and cognitive disorders.

Microglial Branching