Periodized low protein-high carbohydrate diet confers potent, but transient, metabolic improvements

Abstract

ObjectiveChronic ad libitum low protein-high carbohydrate diet (LPHC) increases health- and life-span in mice. A periodized (p) LPHC regimen would be a more practical long-term human lifestyle intervention, but the metabolic benefits of pLPHC are not known. Also, the interactions between LPHC diet and exercise training have not been investigated. Presently, we aimed to provide proof-of-concept data in mice of the efficacy of pLPHC and to explore the potential interactions with concurrent exercise training.MethodsA detailed phenotypic and molecular characterization of mice undergoing different durations of 14 d LPHC (5 E% protein)/14 d control diet cycles for up to 4 months with or without concurrent access to activity wheels allowing voluntary exercise training.ResultspLPHC conferred metabolic benefits similar to chronic LPHC, including increased FGF21 and adaptive thermogenesis, obesity-protection despite increased total energy intake and improved insulin sensitivity. The improved insulin sensitivity showed large fluctuations between diet periods and was lost within 14 days of switching back to control diet. Parallel exercise training improved weight maintenance but impaired the FGF21 response to pLPHC whereas repeated pLPHC cycles progressively augmented this response. Both the FGF21 suppression by exercise and potentiation by repeated cycles correlated tightly with Nupr1 mRNA in liver, suggesting dependence on liver integrated stress response.ConclusionThese results suggest that pLPHC may be a viable strategy to promote human health but also highlight the transient nature of the benefits and that the interaction with other lifestyle-interventions such as exercise training warrants consideration.

The Gut Microbiome on a Periodized Low-Protein Diet Is Associated With Improved Metabolic Health

“…Thus, the phenotype may reflect mainly the impact of the last 14 days on LPHC diet rather than the chronic cumulative effect of being on pLPHC for 12 weeks. Indeed, we found this to be the case for glucose metabolism which was not different in a follow-up pLPHC study ending with 14 days of HFD, suggesting a transient improvement during each LPHC period (Li et al, 2018a). FGF21 induction, however, did show a cumulative effect and was potentiated with each additional pLPHC period, despite returning to baseline in the intertwining HFD periods (Li et al, 2018a).…”

“…Next, we compared our current analysis of the GM to our previous published meta-data on a number of health-related parameters in the same mice (Li et al, 2018a). To briefly sum up our published findings, pLPHC diet mice vs. HFD controls showed improved whole-body glucose tolerance, HOMA2-IR, increased total energy intake but also increased adaptive thermogenesis leading to overall reduced feed efficiency and weight gain-protection, resulting from significant loss of fat mass and tendency to loss of lean body mass.…”

“…We found that mice on pLPHC diet had a GM profile which was overall consistent with a push of the phenotype toward a healthier state. Whether the GM profile is causally related to the host pLPHC diet phenotype, which included obesity-protection despite increased total energy intake due to increased adaptive thermogenesis and increased glucose tolerance and whole-body insulin sensitivity (Li et al, 2018a), is currently unclear. In contrast, concurrent voluntary exercise training had small and statistically insignificant effects on the GM in the current study.…”

“…The overall study design, methods, diet descriptions and a comprehensive metabolic characterization has been published previously (Li et al, 2018a,b). All experiments were pre-approved by the Danish Animal Experimental Inspectorate and complied with the “European Convention for the Protection of Vertebrate Animals Used for Experiments and Other Scientific Purposes.” In brief, retired female C57BL/6J (Janvier, France) breeder mice aged 8–9 months were randomized to either chronic chow diet, low-protein/high-carbohydrate diet, high-protein/low-carbohydrate diet, HFD or a periodized low-protein/high-carbohydrate diet regimen, switching between pLPHC diet and HFD every 14 days.…”

“…In a recent study, we investigated the impact of a periodized 14 days low protein/high carbohydrate (pLPHC) diet/14 days HFD cycles provided for 3 months in conjunction with voluntary running wheel exercise training (termed exercise training from hereon) on obesity-development, whole-body metabolism, insulin sensitivity, and cell signaling in liver and skeletal muscle (Li et al, 2018a). Our control diets included chow, 60% HFD, LPHC diet, and HPLC diet given chronically for 3 months (Li et al, 2018b).…”