Gastric mucosal transcriptomic responses to diet-induced obesity and calorie restriction in mice

The transcriptional landscape of the gastric mucosa during diet-induced obesity (DIO) and calorie restriction (CR) is largely unexplored. Here, we profiled gastric mucosal gene expression changes induced in mice by DIO and CR and investigated the physiological role of Decidual Protein Induced by Progesterone 1 (Depp1) using newly-generated Depp1-knockout (KO) mice. RNA sequencing revealed that DIO predominantly induces a pro-inflammatory transcriptional signature, whereas CR upregulates genes involved in peptide transport and extracellular matrix organization and downregulates immunity-related genes. Among CR-induced genes, Depp1 showed the strongest positive correlation with ghrelin expression. qRT-PCR confirmed that Depp1 expression in the gastric mucosa was restricted to ghrelin cells and demonstrated that CR also induces Depp1 upregulation in other tissues, including kidney, lung, and liver. Hepatic Depp1 upregulation by CR was absent in ghrelin-KO mice. Notably, Depp1-knockout mice displayed normal metabolic and hormonal responses to CR, including the expected rise in circulating ghrelin. However, after 16 weeks of ad libitum high-fat diet feeding, male Depp1-KO mice exhibited greater increases in body weight, food intake, fat mass, and lean mass, as well as reduced glucose tolerance compared with wild-type littermates. These changes were accompanied by altered hepatic expression of the GHSR (ghrelin receptor) antagonist Leap2 and the gluconeogenic gene Pck1. Thus, while Depp1 is a CR-induced, ghrelin cell-regulated gene that modulates hepatic transcriptional responses, it is not required for short-term metabolic adaptation to CR. Instead, Depp1 plays a protective role against the full development of metabolic dysfunction during DIO through mechanisms that remain to be elucidated.