Interplay of peripheral clock genes with energy balance and nutrients: Role of hormonal pathways
Endocrinology, Diabetology, Metabolism
Final Report Abstract
The aim of the project was to investigate the interaction of the circadian system and metabolic processes in body weight regulation. For this, Kramer’s group investigated the mechanism of insulin-mediated modulation of circadian clocks in adipose tissue and a possible role of the clock in adipose tissue for insulin sensitivity. These studies revealed that insulin induces an acute and transient upregulation of PER2 protein expression and phase-shifts the clock in adipose tissue. Further, a transcriptional regulation of the immediate early clock genes per1 and per2 in 3T3L1 adipocytes and an activation of the per2 promoter independently of CRE elements by insulin was shown. Down-regulation of the core clock gene Bmal1 in 3T3L1 adipocytes was established in order to test whether the cellular insulin response via the detection of AKT-phosphorylation is impaired. Preliminary data showed that impairment of the intrinsic clock of adipocytes does not affect insulin sensitivity of adipocytes. In the Pfeiffer’s lab, effects of diurnal distribution of carbohydrates and fat on metabolic parameters and central and peripheral clock were investigated in human dietary intervention study. In this cross-over trial, 29 non-obese men were randomized to two four-week diets: (1) carbohydrate-rich meals in the morning and fat-rich meals in the afternoon (HC/HF) versus (2) inverse sequence of meals (HF/HC). The HF/HC diet shows an unfavourable effect on glycaemic control in subjects with impaired fasting glucose and/or impaired glucose tolerance (IFG/IGT), but not in subjects with normal glucose tolerance. Afternoon decline of glucose tolerance was more pronounced in IFG/IGT and associated with a stronger decrease of postprandial GLP-1 and PYY levels. Consequently, large, carbohydrate-rich dinners should be avoided, primarily by subjects with impaired glucose metabolism. Diurnal distribution of carbohydrates and fat affects daily profiles of substrate oxidation, circulating lipids and cytokine secretion and shifts average daily concentrations of adipokine secretion. Moreover, different dietary patterns induce deep remodeling of circadian transcriptome in human adipose tissue. Taken together, our research revealed novel mechanisms of clock-metabolism interaction in the body weight regulation in humans and lead to the development of dietary recommendations based on the timing of food intake.
Publications
- Changes of dietary fat and carbohydrate content alter central and peripheral clock in humans. J Clin Endocrinol Metab. 2015 Jun;100(6):2291-302
Pivovarova O, Jürchott K, Rudovich N, Hornemann S, Lu Y, Möckel S, Murahovschi V, Kessler K, Seltmann A-C, Maser-Gluth C, Mazuch J, Kruse M, Busjahn A, Kramer A, Pfeiffer AFH
(See online at https://doi.org/10.1210/jc.2014-3868) - Regulation of the clock gene expression in human adipose tissue by weight loss. Int J Obes (Lond). 2016 Jun;40(6):899-906
Pivovarova O, Gögebakan Ö, Sucher S, Groth J, Murahovschi V, Kessler K, Osterhoff M, Rudovich N, Kramer A, Pfeiffer AF
(See online at https://doi.org/10.1038/ijo.2016.34) - The effect of diurnal distribution of carbohydrates and fat on glycaemic control in humans: a randomized controlled trial. Sci Rep. 2017 Mar 8;7:44170
Kessler K, Hornemann S, Petzke KJ, Kemper M, Kramer A, Pfeiffer AFH, Pivovarova O, Rudovich N.
(See online at https://doi.org/10.1038/srep44170)
