Brain JNK and metabolic disease

• Published in: Diabetologia 2021-02, Vol.64 (2), p.265-274
• Main Authors: Nogueiras, Rubén, Sabio, Guadalupe
• Format: Article
• Language: English
• Subjects: Agouti gene; Agouti-Related Protein - metabolism; Animals; Brain - cytology; Brain - metabolism; c-Jun protein; Central nervous system; Diabetes; Diabetes mellitus (non-insulin dependent); Endoplasmic Reticulum Stress; Energy balance; Energy expenditure; Energy Metabolism - physiology; Feeding Behavior - physiology; Glucose - metabolism; Homeostasis; Human Physiology; Humans; Hypothalamo-Hypophyseal System - metabolism; Hypothalamus; Hypothalamus - cytology; Hypothalamus - metabolism; Insulin; Insulin - metabolism; Internal Medicine; JNK Mitogen-Activated Protein Kinases - metabolism; JNK protein; JNK3 protein; Leptin; Leptin - metabolism; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolic Diseases - metabolism; Metabolic disorders; Mitogen-Activated Protein Kinase 10 - metabolism; Mitogen-Activated Protein Kinase 8 - metabolism; Mitogen-Activated Protein Kinase 9 - metabolism; Neurons - cytology; Neurons - metabolism; Obesity; Obesity - metabolism; Overnutrition; Pituitary; Review; Signal transduction; Thyroid; Thyroid Gland - metabolism; Transcription factors; Weight Gain - physiology
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-020-05327-w

Obesity, which has long since reached epidemic proportions worldwide, is associated with long-term stress to a variety of organs and results in diseases including type 2 diabetes. In the brain, overnutrition induces hypothalamic stress associated with the activation of several signalling pathways, together with central insulin and leptin resistance. This central action of nutrient overload appears very rapidly, suggesting that nutrition-induced hypothalamic stress is a major upstream initiator of obesity and associated diseases. The cellular response to nutrient overload includes the activation of the stress-activated c-Jun N-terminal kinases (JNKs) JNK1, JNK2 and JNK3, which are widely expressed in the brain. Here, we review recent findings on the regulation and effects of these kinases, with particular focus on the hypothalamus, a key brain region in the control of energy and glucose homeostasis. JNK1 blocks the hypothalamic–pituitary–thyroid axis, reducing energy expenditure and promoting obesity. Recently, opposing roles have been identified for JNK1 and JNK3 in hypothalamic agouti gene-related protein (AgRP) neurons: while JNK1 activation in AgRP neurons induces feeding and weight gain and impairs insulin and leptin signalling, JNK3 (also known as MAPK10 ) deletion in the same neuronal population produces very similar effects. The opposing roles of these kinases, and the unknown role of hypothalamic JNK2, reflect the complexity of JNK biology. Future studies should address the specific function of each kinase, not only in different neuronal subsets, but also in non-neuronal cells in the central nervous system. Decoding the puzzle of brain stress kinases will help to define the central stimuli and mechanisms implicated in the control of energy balance. Graphical abstract