Insulin receptor in the brain: Mechanisms of activation and the role in the CNS pathology and treatment

Abstract

While the insulin receptor (IR) was found in the CNS decades ago, the brain was long considered to be an insulin-insensitive organ. This view is currently revisited, given emerging evidence of critical roles of IR-mediated signaling in development, neuroprotection, metabolism, and plasticity in the brain. These diverse cellular and physiological IR activities are distinct from metabolic IR functions in peripheral tissues, thus highlighting region specificity of IR properties. This particularly concerns the fact that two IR isoforms, A and B, are predominantly expressed in either the brain or peripheral tissues, respectively, and neurons express exclusively IR-A. Intriguingly, in comparison with IR-B, IR-A displays high binding affinity and is also activated by low concentrations of insulin-like growth factor-2 (IGF-2), a regulator of neuronal plasticity, whose dysregulation is associated with neuropathologic processes. Deficiencies in IR activation, insulin availability, and downstream IR-related mechanisms may result in aberrant IR-mediated functions and, subsequently, a broad range of brain disorders, including neurodevelopmental syndromes, neoplasms, neurodegenerative conditions, and depression. Here, we discuss findings on the brain-specific features of IR-mediated signaling with focus on mechanisms of primary receptor activation and their roles in the neuropathology. We aimed to uncover the remaining gaps in current knowledge on IR physiology and highlight new therapies targeting IR, such as IR sensitizers.

Metabolic, Molecular, and Behavioral Effects of Western Diet in Serotonin Transporter-Deficient Mice: Rescue by Heterozygosity?

“…The latter results in impaired glucose tolerance, decreased metabolic rate, and obesity (Kahn and Flier, 2000;Wellen and Hotamisligil, 2003). Thus, a close functional relationship between decreased SERT function, pro-inflammatory changes, and insulin resistance is supported by the existing literature (Haub et al, 2010;Pomytkin et al, 2015Pomytkin et al, , 2018.…”

“…Serotonin transporter (SERT), a key element of serotonergic neurotransmission (Collier et al, 1996;Murphy et al, 2004), is also involved in the regulation of metabolic processes (Stuart and Baune, 2012;Giannaccini et al, 2013;Pomytkin et al, 2015Pomytkin et al, , 2018. In humans, a variant of the upstream regulatory region of the SERT (SLC6A4) gene, the so-called short (s) allele, in comparison with long (l) allele is associated with lower SERT activity and stressed-related vulnerability to anxiety and depression (Lesch et al, 1996;Greenberg et al, 2000;Caspi et al, 2010), and also with higher body mass index (BMI) (Sookoian et al, 2007;Fuemmeler et al, 2008) and incidence of type-2 diabetes (Iordanidou et al, 2010), which are typical for the female sex and aging (Kautzky-Willer et al, 2016;Khabazkhoob et al, 2017;Batsis and Zagaria, 2018).…”

“…Excessive intake of a hypercaloric diet, enriched with saturated fat and sugars, was shown to suppress the binding of hypothalamic SERT in obese subjects and in insulin-resistant subjects that is independent of body weight gain (Koopman et al, 2013;Versteeg et al, 2017). Thus, diminished SERT activity is believed to underlie negative changes associated with metabolic syndrome (Stuart and Baune, 2012) and in turn, metabolic abnormalities resulting in reduced SERT function that can contribute to emotional disturbances (Pomytkin et al, 2015(Pomytkin et al, , 2018.…”

Serum insulin‐like growth factor‐1 levels in neurodegenerative diseases

“…Additionally, a study with posttraumatic epilepsy models showed that IGF‐1 treatment can be beneficial or harmful depending on the stage of the disease . Therefore, it is important to assess serum IGF‐1 levels and their clinical correlations in various neurodegenerative diseases in which IGF signaling and its receptors in the brain are involved . We found a negative correlation of serum IGF‐1 with age in AD, PD, ALS, and DLB patients.…”

The impact of anorexigenic peptides in experimental models of Alzheimer’s disease pathology

“…Disturbances in insulin signaling appear to be the main common impairment that affects cell growth and differentiation, cellular repair mechanisms, energy metabolism and glucose utilization. Insulin not only regulates blood glucose levels but also acts as a growth factor on all cells, including neurons in the CNS (Pomytkin et al 2018).…”