Role of cardiotrophin-1 in the regulation of metabolic circadian rhythms and adipose core clock genes in mice and characterization of 24-h circulating CT-1 profiles in normal-weight and overweight/obese subjects

Abstract

Cardiotrophin (CT)-1 is a regulator of glucose and lipid homeostasis. In the present study, we analyzed whether CT-1 also acts to peripherally regulate metabolic rhythms and adipose tissue core clock genes in mice. Moreover, the circadian pattern of plasma CT-1 levels was evaluated in normal-weight and overweight subjects. The circadian rhythmicity of oxygen consumption rate (Vo₂) was disrupted in aged obese CT-1-deficient (CT-1^-/-) mice (12 mo). Although circadian rhythms of Vo₂ were conserved in young lean CT-1^-/- mice (2 mo), CT-1 deficiency caused a phase shift of the acrophase. Most of the clock genes studied (Clock, Bmal1, and Per2) displayed a circadian rhythm in adipose tissue of both wild-type (WT) and CT-1^-/- mice. However, the pattern was altered in CT-1^-/- mice toward a lower percentage of the rhythm or lower amplitude, especially for Bmal1 and Clock. Moreover, CT-1 mRNA levels in adipose tissue showed significant circadian fluctuations in young WT mice. In humans, CT-1 plasma profile exhibited a 24-h circadian rhythm in normal-weight but not in overweight subjects. The 24-h pattern of CT-1 was characterized by a pronounced increase during the night (from 02:00 to 08:00). These observations suggest a potential role for CT-1 in the regulation of metabolic circadian rhythms.-López-Yoldi, M., Stanhope, K. L., Garaulet, M., Chen, X. G., Marcos-Gómez, B., Carrasco-Benso, M. P., Santa Maria, E. M., Escoté, X., Lee, V., Nunez, M. V., Medici, V., Martínez-Ansó, E., Sáinz, N., Huerta, A. E., Laiglesia, L. M., Prieto, J., Martínez, J. A., Bustos, M., Havel, P. J., Moreno-Aliaga, M. J. Role of cardiotrophin-1 in the regulation of metabolic circadian rhythms and adipose core clock genes in mice and characterization of 24-h circulating CT-1 profiles in normal-weight and overweight/obese subjects.

Keywords: Bmal1; Cry1; Per2; adipose tissue; obesity.

Figure 1.

Cosinor analysis of the 24-h circadian rhythm for Vo₂ in WT and CT-1^−/− mice at 2 and 12 mo of age. Top: polar (clock-like) representation of the estimates of the parameters of the rhythm for Vo₂ in the form of a 24-h clock in WT and CT-1^−/− mice at 2 (A) and 12 (B) mo of age. Bottom: x–y plot showing the best-fitting waveform profile of the rhythm.

Figure 2.

Daily mRNA expression profiles and cosinor analysis of the circadian rhythms for core clock genes. Left: around the clock gene expression levels of Clock (A), Bmal1 (B), Per2 (C), and Cry1 (D) in epididymal fat of 2-mo-old WT and CT-1^−/− mice. Data are means ± sem (n = 4–6). Polar (clock-like) representation of the estimates of the parameters of the rhythm for clock genes in the form of a 24-h clock in WT (middle panels) and CT-1^−/− (right panels) mice at 2 mo of age. *P < 0.05 vs. WT control group.

Figure 3.

Adipose tissue daily mRNA expression profile and cosinor analysis of CT-1. Around the clock gene expression levels of CT-1 in epididymal fat of 2-mo-old WT mice. Data are means ± sem (n = 4–6). Polar (clock-like) representation of the estimates of the parameters of the rhythm for CT-1 mRNA in the form of a 24-h clock in WT mice at 2 mo of age.

Figure 4.

Circadian CT-1 plasma profile in humans. A) Plasma 24-h CT-1 profile in normal-weight (n = 6) and overweight (n = 5) groups. Plasma CT-1 levels are expressed as a percentage relative to 24-h mean. Data are means ± sem. *P < 0.05, vs. normal weight. B) Cosinor analysis of the circadian rhythm for plasma CT-1 in normal-weight and overweight subjects. Top: polar (clock-like) representation of the estimates of the parameters of the rhythm for plasma CT-1 in the form of a 24-h clock in normal-weight and overweight subjects. Bottom: x–y plots showing the best fitting waveform profile of the rhythm in normal-weight and overweight subjects.