http://www.the-scientist.com/?articles.view/articleNo/33338/title/Metabolism-and-the-Brain/
http://www.the-scientist.com/?articles.view/articleNo/33338/title/Metabolism-and-the-Brain/
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The metabolic link
The association between disruptions in glucose metabolism and psychiatric disorders was first documented more than 3 centuries ago by the English doctor Thomas Willis. He noted that persons who had experienced stressful life events, depression, or “long sorrow,” often suffered from diabetes. Years later, in 1897, British psychiatrist Henry Maudsley observed that diabetes and insanity are often co-expressed in families, and in 1935, American psychiatrist William Claire Menninger postulated the existence of psychogenic diabetes and described a “diabetic personality.” More recently, researchers suggested that enhancing glucose metabolism and related insulin-signaling pathways in the brain improved functional activity of patients with schizophrenia. ...
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INFLAMMATION
One common physiological process that may be influenced by insulin-mediated signaling and involved in the pathogenesis of both neuropsychiatric and metabolic disorders is inflammation. Abnormal levels of immunomodulating agents, such as cytokines, are associated with inflammatory processes in the brain and peripheral organs, and studies in humans and rodents have demonstrated that chronic inflammation may be a key factor in the pathogenesis of both types of disorders.
The link between inflammation and diseases of the brain is no surprise. Higher-than-normal levels of circulating inflammatory cytokines, together with activated astrocytes and microglia in the brain, are found in patients with Parkinson’s, Alzheimer’s, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and mood disorders. Cytokines have the capacity to influence the synthesis, release, and reuptake of neurotransmitters, such as dopamine and serotonin. Likely for this reason, antidepressants that target these systems are less effective in individuals with an active inflammatory state, and antidepressant efficiency may be enhanced when combined with anti-inflammatory agents, such as aspirin (acetylsalicylic acid). Furthermore, the injection of a bacterial endotoxin, which activates pro- as well as anti-inflammatory cytokines, into healthy volunteers induces depressive symptoms and verbal and nonverbal memory deficits. Similarly, the systemic administration of pro-inflammatory cytokines in rodents induces “sickness behavior,” including anorexia, sleep disturbance, neurocognitive impairment, fatigue, and reduced self-care behaviors.
Evidence supporting inflammation as a possible link between brain and metabolic disorders comes from fat tissue–derived cytokines called adipokines. One such adipokine, leptin, has been found to be elevated in patients with depression, and postmortem studies of depressed patients who committed suicide revealed a downregulation of leptin receptors in the frontal cortex. On the metabolism side of the coin, obesity is classified as a state of chronic low-grade inflammation1 and is associated with abnormal levels of adipokines.2 (See “Fat's Immune Sentinels”) For example, mice with a mutation in the leptin or leptin receptor gene have demonstrated deficits in cell-mediated immunity, and are obese and diabetic. In addition, animal studies have demonstrated that Toll-like receptor (TLR) signaling, which is a fundamental component in the innate immune system response, is implicated in mediating insulin and leptin resistance in the brain.
STRESS
Stress is another condition that is influenced by insulin-mediated signaling and may be an additional link between metabolic and neurological disturbances. Whether it be hunger, childhood adversity, or challenging life events, stress has been implicated in the development of obesity as well as addiction and other psychiatric disorders.
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The way forward
Normal and pathological conditions have an immediate impact on brain functions. Moreover, neurons and glial cells exist in a tight, mutual structure-function relationship that is highly dependent on the peripheral supply of glucose—the cells’ major energy source. Converging evidence indicates that insulin serves several critical roles in the CNS under both normal and abnormal conditions. Insulin receptors are expressed in the brain, affecting a wide range of normal brain functions, such as reward, motivation, cognition, attention, and memory formation, and dysregulation of insulin signaling leads to characteristic signs of neurodegenerative and psychiatric diseases. Thus, pharmacological targeting of insulin-mediated signaling pathways may be beneficial in treating brain disorders.
Furthermore, the totality of evidence suggests that metabolic and neuropsychiatric disorders may share a common pathophysiological nexus. Critical effectors of this association include alterations in whole-body energy metabolism, oxidative stress, inflammation, insulin resistance, and corticosteroid signaling, as well as imbalances in cytokines and adipokines. Investigations that aim to refine the relative contributions of these effector systems, with a particular focus on convergent molecular pathways, may provide the basis for disease-related biomarker discovery, as well as novel treatment approaches for both metabolic and neuropsychiatric conditions.
http://www.the-scientist.com/?articles.view/articleNo/33338/title/Metabolism-and-the-Brain/
