Chronic sleep loss and circadian disruption can impair metabolic functions in humans, and both sleep and circadian rhythmicity are disrupted with aging. Furthermore, sleep loss itself often leads to disruptions of circadian rhythmicity, and disrupted circadian rhythmicity can induce sleep loss. In Project 3, we will use mouse models to dissociate these two influences so as to better understand their independent impacts on metabolism and to study the physiological and molecular mechanisms mediating those metabolic effects.
Aim 1 will study the changes in feeding, body weight, plasma levels of various metabolic markers and glucose tolerance and insulin sensitivity (whole body and fat tissue) in young and older mice experiencing chronic sleep loss following genetic lesions of galaninergic (GAL) neurons in the ventrolateral preoptic area (VLPO). We will also assess corticosteroid secretion and sympathovagal balance in these mice in order to study the physiological mechanisms contributing to the changes in insulin sensitivity. Finally, in Aim 1, we will trace the specific projections of GAL and non-GAL neurons in the VLPO to determine which of these neurons have connections with sites involved in energy metabolism, corticosteroid section and sympathovagal balance.
In Aim 2, we will study the same metabolic outcomes as in Aim 1 of recurrent circadian disruption (RCD) achieved by exposing C57 mice (young and older) to a 10:10 LD cycle for 12 weeks and investigating the effects of feeding periods synchronized with either body temperature (Tb) or locomotor activity (LMA) rhythms) in attenuating the adverse metabolic effects. To understand the molecular mechanisms underlying these changes, in Aim 3, we will study changes in the phase and amplitude of central and peripheral clocks and the downstream changes in gene expression (by histone deacetylase 3 ChlP-seq) they drive in the peripheral tissues when the transgenic PER2::LUC mice (both young and older) are maintained on a 10:10 LD cycle and on each of the 3 different feeding regimens as in Aim 2 (unrestricted access to food or feeding synchronized with their LD or Tb cycle).

Public Health Relevance

The prevalence of obesity and diabetes is increasing rapidly worldwide. This study addresses the important question of how 'novel'life style factors (apart from diet and physical activity), such as sleep curtailment and an inconsistent bedtime (shift work), contribute to the development of obesity and diabetes.

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
5P01AG009975-17
Application #
8707297
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
Budget End
Support Year
17
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
Markt, Sarah C; Valdimarsdottir, Unnur A; Shui, Irene M et al. (2015) Circadian clock genes and risk of fatal prostate cancer. Cancer Causes Control 26:25-33
Balasubramanian, Ravikumar; Cohen, Daniel A; Klerman, Elizabeth B et al. (2014) Absence of central circadian pacemaker abnormalities in humans with loss of function mutation in prokineticin 2. J Clin Endocrinol Metab 99:E561-6
Dean 2nd, Dennis A; Adler, Gail K; Nguyen, David P et al. (2014) Biological time series analysis using a context free language: applicability to pulsatile hormone data. PLoS One 9:e104087
Hsieh, Wan-Hsin; Escobar, Carolina; Yugay, Tatiana et al. (2014) Simulated shift work in rats perturbs multiscale regulation of locomotor activity. J R Soc Interface 11:
Lim, Andrew S P; Ellison, Brian A; Wang, Joshua L et al. (2014) Sleep is related to neuron numbers in the ventrolateral preoptic/intermediate nucleus in older adults with and without Alzheimer's disease. Brain 137:2847-61
Lee, Jung Hie; Kim, Seong Jae; Lee, Se Yong et al. (2014) Reliability and validity of the Korean version of Morningness-Eveningness Questionnaire in adults aged 20-39 years. Chronobiol Int 31:479-86
Faghih, Rose T; Dahleh, Munther A; Adler, Gail K et al. (2014) Deconvolution of serum cortisol levels by using compressed sensing. PLoS One 9:e85204
Phillips, A J K; Fulcher, B D; Robinson, P A et al. (2013) Mammalian rest/activity patterns explained by physiologically based modeling. PLoS Comput Biol 9:e1003213
Breslow, Emily R; Phillips, Andrew J K; Huang, Jean M et al. (2013) A mathematical model of the circadian phase-shifting effects of exogenous melatonin. J Biol Rhythms 28:79-89
Phillips, A J K; Robinson, P A; Klerman, E B (2013) Arousal state feedback as a potential physiological generator of the ultradian REM/NREM sleep cycle. J Theor Biol 319:75-87

Showing the most recent 10 out of 128 publications