Kinase Suppressor of Ras 2 (KSR2) expression in the brain regulates energy balance and glucose homeostasis
| Autor: | Richard G. MacDonald, Diane L. Costanzo-Garvey, Beth K. Neilsen, Lili Guo, Robert E. Lewis, Deandra R. Smith |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male AMPK medicine.medical_specialty lcsh:Internal medicine medicine.medical_treatment Carbohydrate metabolism Biology Fatty Acids Nonesterified Protein Serine-Threonine Kinases 03 medical and health sciences Mice Insulin resistance Internal medicine medicine Glucose homeostasis Animals Homeostasis Insulin Obesity lcsh:RC31-1245 Molecular Biology 2. Zero hunger Mice Knockout Glucose metabolism Kinase KSR2 Leptin Brain Cell Biology Ribonucleotides medicine.disease Aminoimidazole Carboxamide 030104 developmental biology Endocrinology Glucose Female Original Article Energy Metabolism Signal Transduction |
| Zdroj: | Molecular Metabolism, Vol 6, Iss 2, Pp 194-205 (2017) Molecular Metabolism |
| ISSN: | 2212-8778 |
| Popis: | Objective Kinase Suppressor of Ras 2 (KSR2) is a molecular scaffold coordinating Raf/MEK/ERK signaling that is expressed at high levels in the brain. KSR2 disruption in humans and mice causes obesity and insulin resistance. Understanding the anatomical location and mechanism of KSR2 function should lead to a better understanding of physiological regulation over energy balance. Methods Mice bearing floxed alleles of KSR2 (KSR2fl/fl) were crossed with mice expressing the Cre recombinase expressed by the Nestin promoter (Nes-Cre) to produce Nes-CreKSR2fl/fl mice. Growth, body composition, food consumption, cold tolerance, insulin and free fatty acid levels, glucose, and AICAR tolerance were measured in gender and age matched KSR2−/− mice Results Nes-CreKSR2fl/fl mice lack detectable levels of KSR2 in the brain. The growth and onset of obesity of Nes-CreKSR2fl/fl mice parallel those observed in KSR2−/− mice. As in KSR2−/− mice, Nes-CreKSR2fl/fl are glucose intolerant with elevated fasting and cold intolerance. Male Nes-CreKSR2fl/fl mice are hyperphagic, but female Nes-CreKSR2fl/fl mice are not. Unlike KSR2−/− mice, Nes-CreKSR2fl/fl mice respond normally to leptin and AICAR, which may explain why the degree of obesity of adult Nes-CreKSR2fl/fl mice is not as severe as that observed in KSR2−/− animals. Conclusions These observations suggest that, in the brain, KSR2 regulates energy balance via control of feeding behavior and adaptive thermogenesis, while a second KSR2-dependent mechanism, functioning through one or more other tissues, modulates sensitivity to leptin and activators of the energy sensor AMPK. Highlights • Brain-specific KSR2 knockout causes obesity and glucose intolerance in both genders, but hyperphagia only in male mice. • Brain-specific KSR2 knockout suppresses body temperature, before obesity. • KSR2 in the brain regulates energy balance via control of feeding behavior and adaptive thermogenesis. |
| Databáze: | OpenAIRE |
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