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High-fat dietary restriction in mice induces substrate efficiency and improves metabolic health

ABSTRACT: High energy intake and, specifically, high dietary fat intake challenges the mammalian metabolism and correlates with many metabolic disorders, such as obesity and diabetes. Dietary restriction (DR) is, on the other hand, known to prevent the development of metabolic disorders. The current Western diets are highly enriched in fat and it is as yet unclear whether DR on a certain high-fat (HF) diet elicits similar beneficial effects on health. Here, we report that HF-DR improves metabolic health of mice, compared to mice receiving the same diet on an ad-libitum basis (HF-AL). Already after five weeks of restriction the serum levels of cholesterol and leptin were significantly decreased in HF-DR mice, while their glucose sensitivity and serum adiponectin levels were increased. The body weight and measured serum parameters remained stable in the following 7 weeks of restriction, implying metabolic adaptation. To understand the molecular events associated with this adaptation, we analysed gene expression in white adipose tissue (WAT) with whole genome microarrays. HF-DR strongly influenced gene expression in WAT; in total 8,643 genes were differentially expressed between both groups of mice, with a major role for genes involved in lipid metabolism and mitochondrial functioning. This was confirmed by qRT-PCR and substantiated by an increase in mitochondrial density in WAT of HF-DR mice. These results provide new insights in the metabolic flexibility of dietary restricted animals and suggest the development of substrate efficiency. Limiting food intake by decreasing portion sizes, while maintaining energy sufficiency, may similarly benefit metabolic health in humans.

ORGANISM(S): Mus musculus

PROVIDER: GSE27213 | GEO | 2011/08/24

SECONDARY ACCESSION(S): PRJNA137517

REPOSITORIES: GEO

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Project description:Aims/hypothesis: Dietary restriction (DR) reduces adiposity and improves metabolism in patients with one or more symptoms of the metabolic syndrome. Nonetheless, it remains elusive whether the benefits of DR in humans are mediated by calorie or nutrient restriction. This study was conducted to identify whether isocaloric dietary protein restriction is sufficient to confer the beneficial effects of dietary restriction in patients with metabolic syndrome. Methods: We performed a prospective, randomized controlled dietary intervention under constant nutritional and medical supervision. A total of 21 individuals diagnosed with the metabolic syndrome was randomly assigned for caloric restriction (CR; n = 11, mean age 49 ± 8.5 years, female 63%; diet of 5,941 ± 686 KJ per day) or isocaloric dietary protein restriction (PR; n = 10, mean age 51.6 ± 8.9 years, female 50%; diet of 8,409 ± 2,360 KJ per day) and followed for 27 days. Results: Like CR, PR promoted weight loss (-6.6%, P= 0.0041) due to reduction in adiposity (-9.9%, P= 0.0007), associated with reductions in blood glucose (-52.7%, P= 0.0002), lipid levels (cholesterol, -35.4%, P= 0.0010; triglycerides, -39.5% P= 0.0022) and blood pressure (systolic, -37.7 P< 0.0001; diastolic, -73.2% P< 0.0001). PR resulted in enrichment of metabolic pathways related to the immune system such as B cell proliferation, lymphocyte proliferation and leukocyte proliferation in subcutaneous adipose tissue. Hence, a reduction in calorie intake or changes in the gut microbiome are not necessary to confer the metabolic benefits of DR. Instead, a reduction in protein intake with a mild increase in carbohydrate intake to maintain the isocaloric balance of the diet is sufficient to improve metabolic control. Conclusions/interpretation: Protein restriction is sufficient to confer almost the same clinical outcomes as calorie restriction without the need for a reduction in calorie intake. The isocaloric characteristic of the PR intervention makes this approach a more attractive and less drastic dietary strategy in clinical settings and has greater potential to be used as adjuvant therapy for people with the metabolic syndrome.

Project description:We previously reported that a low versus high glycemic index (GI) diet on a high fat (30% kcal fat) background (LGI and HGI, respectively) significantly retarded adverse health effects in C57BL/6J male mice. The LGI diet enhanced whole body insulin sensitivity and repressed high fat diet-induced body and adipose tissue weight gain, resulting in reduced serum leptin and resistin levels (Faseb J 2009; 23: 1092-1101). How white adipose tissue (WAT) is effected is examined in the present study. We characterized the molecular mechanisms underlying the GI-mediated effects in WAT using whole genome transcriptomics technology. We show that a LGI vs. HGI diet mainly exerts its beneficial effects on substrate metabolism, especially insulin signaling of fatty acid metabolism. In addition, cell adhesion and cytoskeleton remodeling showed reduced expression in line with lower WAT mass, but it might also be due to altered insulin sensitivity. An important transcription factor showing enhanced expression is PPARgamma. Furthermore, serum levels of triglycerides, total cholesterol, HDL- and LDL-cholesterol were significantly reduced by a LGI vs. HGI diet, and muscle insulin sensitivity was significantly increased as analyzed by PKB/Akt phosphorylation. Cumulatively, even though these mice were fed a high fat diet, the low versus high GI induced significantly favorable changes in metabolism in WAT. These effects suggest a partial overlap with pharmacological approaches by thiazolidinediones (TZDs) to treat insulin resistance and statins and plantsterols/stanols for hypercholesterolemia. It is therefore tempting to speculate that such a dietary approach might beneficially support pharmacological treatment of insulin resistance or hypercholesterolemia in humans. We analyzed 19 epididymal whie adipose tissue (epiWAT) samples from a 13 week High fat diet, Low glycemic index dietary group (LGI, n=9) versus a High fat diet, High glycemic index dietary group (HGI, n=10) after 13 weeks of feeding wildtype C57BL/6J male adult mice. Of the 19 arrays, we excluded 2 arrays for downstream analysis based on quality control (total final set contains 8 LGI and 9 HGI samples).

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High-fat dietary restriction in mice induces substrate efficiency and improves metabolic health

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