The role of MCH/MCHR1 signaling in controlling adipogenesis via the primary cilium

Abstract

The primary cilium functions as a cellular antenna, detecting extracellular stimuli that are important in maintaining tissue function and homeostasis. A prime example of a tissue reacting dynamically to changes in energy homeostasis is the white adipose tissue (WAT). WAT expansion by hyperplasia relies on ciliated adipocyte progenitor cells (APCs) differentiating into mature adipocytes, a process termed adipogenesis. Melanin-concentrating hormone (MCH) signaling via the MCH receptor 1 (MCHR1) is involved in controlling energy homeostasis. MCHR1 localizes to the primary cilia of differentiating APCs but not to the primary cilium of undifferentiated APCs. The orexigenic effect of MCH signaling in the central nervous system has long been known, whereas the role of MCH signaling in APCs remains contested. The Bardet-Biedl Syndrome (BBS) is a ciliopathy characterized, among other symptoms, by central obesity. In BBS mouse models, a lack of ciliary MCHR1 has been observed. A subsequent disturbance of energy homeostasis has been hypothesized to contribute to the BBS phenotype. The Bbs8-/- mouse model recapitulates the obese phenotype. Here, I demonstrate that MCH stimulation inhibits adipogenesis in 3T3-L1 cells, an immortalized cell line that can be differentiated into mature adipocytes, and primary murine APCs. The inhibitory effect of MCH signaling is more potent when applied during differentiation, highlighting the relevance of MCHR1 localization to the primary cilium. Live-cell imaging revealed that MCH stimulation of 3T3-L1 cells decreases the concentration of ciliary cAMP. RNA sequencing revealed that upon MCH stimulation the early adipogenesis marker Klf5 is downregulated in Bbs8+/+ but not in Bbs8-/- cells. The transcription factor Hbp1 is upregulated in Bbs8-/- cells during differentiation, which might contribute to the hypertrophic phenotype of Bbs8-/- cells. In summary, my results indicate that peripheral MCH signaling deceases the ciliary cAMP concentration in APCs, thereby opposing the orexigenic effect of central MCH signaling by limiting WAT expansion. Impaired MCH signaling in Bbs8-/- APCs might contribute to the obese phenotype observed in Bbs8-/- mice.