Intestinal metabolic regulatory mechanisms of the plateau-endemic Sinocyclocheilus grahami in response to long-term starvation

The ability to tolerate starvation is fundamental for animals inhabiting nutrient-limited environments and serves as a critical indicator of fitness, involving multi-level coordination from phenotypic to genomic adaptations. The genus Sinocyclocheilus is endemic to Southwest China, exclusively inhabiting oligotrophic caves and entrance pools ecosystems during at least one life history stage. Thus, it represents an emerging model of metabolic adaptations to food scarcity and the evolutionary mechanisms underlying starvation resistance. In this study, the phenotypic and molecular responses of Sinocyclocheilus grahami to starvation were systematically investigated using histology, electron microscopy, and intestinal comparative transcriptomics analyses. The results showed that prolonged starvation induced slow weight loss accompanied by significant intestinal atrophy, including a reduced intestinal index and shortened villi. Notably, despite significant reductions in mitochondrial morphometry, cristae integrity was maintained without autophagosome formation, indicating metabolic stability. Transcriptomic analysis revealed a unique starvation adaptation strategy: (1) energy conservation by suppressing or shutting down high energy-demand and basal pathways (glycolysis/gluconeogenesis, TCA cycle, and cholesterol synthesis); (2) selective upregulation of key genes involved in glutamine metabolism and protein synthesis to sustain basal physiological functions; and (3) upregulated intestinal lipogenesis. This orchestrated metabolic reprogramming, exhibits a paradoxical anabolic-catabolic pattern that contrasts with the typical starvation response observed in most vertebrates. These findings strongly suggest that the exceptional starvation resistance of S. grahami evolved through long-term adaptation to nutrient-deprived environments. Furthermore, this study provides crucial insights into the evolutionary mechanisms underlying the remarkable species diversity within the genus Sinocyclocheilus and the adaptive strategies for survival in cave ecosystems and analogous oligotrophic habitats. • Slow weight loss accompanied by significant intestinal atrophy were identified. • Energy conservation by suppressing high energy-demand and basal pathways. • Enhanced protein synthesis and lipogenesis sustain basal physiological functions. • Paradoxical anabolic-catabolic pattern contrasts with typical vertebrate starvation. • S. grahami evolved through long-term adaptation to nutrient-deprived environments.