Loss of the calorie restriction response protein DEPP1 worsens diet-induced obesity

The transcriptional landscape of the gastric mucosa in response to opposing nutritional states remains poorly defined. Here, we profiled gastric mucosal gene expression changes induced by diet-induced obesity (DIO) and calorie restriction (CR) in mice 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 elicits a predominantly proinflammatory transcriptional program in the gastric mucosa, whereas CR upregulates genes involved in peptide transport and extracellular matrix organization while downregulating immunity-related pathways. Among CR-induced genes, Depp1 exhibited the strongest positive correlation with expression of gene encoding the gastric hormone ghrelin. qRT-PCR confirmed enrichment of Depp1 in gastric ghrelin cells and demonstrated CR-induced upregulation of Depp1 in additional tissues, including liver, kidney, and pancreas; notably, hepatic induction by CR was absent in ghrelin-KO mice. Despite this association, Depp1-KO mice displayed normal metabolic responses to CR, including preserved glucose homeostasis. In contrast, following 16 weeks of ad libitum high-fat diet feeding, male Depp1-KO mice exhibited greater weight gain, hyperphagia, increased fat and lean mass, and impaired glucose tolerance compared with wild-type littermates. These phenotypes were accompanied by selective hepatic gene expression changes affecting Pgc1a, Pck1, and Igf1. Collectively, these findings identify Depp1 as a CR-induced, ghrelin-associated gene that influences hepatic transcriptional responses yet is dispensable for short-term adaptation to CR, while also implicating Depp1 as a protective factor against metabolic dysfunction during DIO through mechanisms that remain to be defined.