Developmental specification of metabolic circuitry

Elson, Amanda E.T.; Simerly, Richard B.

doi:10.1016/j.yfrne.2015.09.003

Cited by 23 publications

(17 citation statements)

References 204 publications

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“…However, by 8–9 months of age, no differences in these neuropeptides were observed between WT and KSR2 −/− mice, on the DBA1Lac/J background [5] . These seemingly conflicting data may reveal a role for KSR2 in regulating the rate at which neuronal connections are formed in the brain, which can have a potent impact on the development of neural control over energy balance [21] .…”

Section: Discussionmentioning

confidence: 99%

Kinase Suppressor of Ras 2 (KSR2) expression in the brain regulates energy balance and glucose homeostasis

Guo

Costanzo-Garvey

Smith

et al. 2017

Molecular Metabolism

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ObjectiveKinase 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.MethodsMice 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−/− miceResultsNes-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.ConclusionsThese 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.

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Section: Discussionmentioning

confidence: 99%

Kinase Suppressor of Ras 2 (KSR2) expression in the brain regulates energy balance and glucose homeostasis

Guo

Costanzo-Garvey

Smith

et al. 2017

Molecular Metabolism

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“…Nutritional interventions as overfeeding or food restriction during the lactation period, or mother´s malnutrition can affect the expression of several elements involved in the activity of the HPT axis (67)(68)(69). Indirect effects on the development of TRHergic neurons may also occur by defects in their innervations since projections from the arcuate nucleus do not reach the PVN until the second postnatal week, and those arising from the brain stem until the end of the third week (65,70).…”

Section: Discussionmentioning

confidence: 99%

Neonatal Maternal Separation Alters, in a Sex-Specific Manner, the Expression of TRH, of TRH-Degrading Ectoenzyme in the Rat Hypothalamus, and the Response of the Thyroid Axis to Starvation

et al. 2016

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Hypothalamic-pituitary-thyroid (HPT) axis activity is important for energy homeostasis, and is modified by stress. Maternal separation (MS) alters the stress response and predisposes to metabolic disturbances in the adult. We therefore studied the effect of MS on adult HPT axis activity. Wistar male and female pups were separated from their mothers 3 h/d during postnatal day (PND)2-PND21 (MS), or left nonhandled (NH). Open field and elevated plus maze tests revealed increased locomotion in MS males and anxiety-like behavior in MS females. At PND90, MS females had increased body weight gain, Trh expression in the hypothalamic paraventricular nucleus, and white adipose tissue mass. MS males had increased expression of TRH-degrading enzyme in tanycytes, reduced TSH and T3, and enhanced corticosterone serum concentrations. MS stimulated brown adipose tissue deiodinase 2 activity in either sex. Forty-eight hours of fasting (PND60) augmented serum corticosterone levels similarly in MS or NH females but more in MS than in NH male rats. MS reduced the fasting-induced drop in hypothalamic paraventricular nucleus-Trh expression of males but not of females and abolished the fasting-induced increase in Trh expression in both sexes. Fasting reduced serum concentrations of TSH, T4, and T3, less in MS than in NH males, whereas in females, TSH decreased in MS but not in NH rats, but T4 and T3 decreased similarly in NH and MS rats. In conclusion, MS produced long-term changes in the activity of the HPT axis that were sex specific; response to fasting was partially blunted in males, which could affect their adaptive response to negative energy balance.

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“…Some of the basic body functions regulated by pituitary hormones and their targets in the adrenal glands, thyroid and gonads include fluid balance, stress response, reproduction and growth. In addition, the hypothalamus makes neural connections via the autonomic nervous system and other pathways to regulate sleep, body temperature and feeding (Elson and Simerly, 2015;Caron and Richard, 2016;Morrison, 2016;Herrera et al, 2017). Because it also receives neuronal and circulatory input from the entire body, the hypothalamus has been seen as a center for responding to the body's physiological status through these hormonal and neural outputs.…”

Section: Introductionmentioning

confidence: 99%

Development of the hypothalamus: conservation, modification and innovation

2017

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The hypothalamus, which regulates fundamental aspects of physiological homeostasis and behavior, is a brain region that exhibits highly conserved anatomy across vertebrate species. Its development involves conserved basic mechanisms of induction and patterning, combined with a more plastic process of neuronal fate specification, to produce brain circuits that mediate physiology and behavior according to the needs of each species. Here, we review the factors involved in the induction, patterning and neuronal differentiation of the hypothalamus, highlighting recent evidence that illustrates how changes in Wnt/β-catenin signaling during development may lead to species-specific form and function of this important brain structure.

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Developmental specification of metabolic circuitry

Cited by 23 publications

References 204 publications

Kinase Suppressor of Ras 2 (KSR2) expression in the brain regulates energy balance and glucose homeostasis

Kinase Suppressor of Ras 2 (KSR2) expression in the brain regulates energy balance and glucose homeostasis

Neonatal Maternal Separation Alters, in a Sex-Specific Manner, the Expression of TRH, of TRH-Degrading Ectoenzyme in the Rat Hypothalamus, and the Response of the Thyroid Axis to Starvation

Development of the hypothalamus: conservation, modification and innovation

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