Effect of one month duration ketogenic and non-ketogenic high fat diets on mouse brain bioenergetic infrastructure

Abstract

Diet composition may affect energy metabolism in a tissue-specific manner. Using C57Bl/6J mice, we tested the effect of ketosis-inducing and non-inducing high fat diets on genes relevant to brain bioenergetic infrastructures, and on proteins that constitute and regulate that infrastructure. At the end of a one-month study period the two high fat diets appeared to differentially affect peripheral insulin signaling, but brain insulin signaling was not obviously altered. Some bioenergetic infrastructure parameters were similarly impacted by both high fat diets, while other parameters were only impacted by the ketogenic diet. For both diets, mRNA levels for CREB, PGC1α, and NRF2 increased while NRF1, TFAM, and COX4I1 mRNA levels decreased. PGC1β mRNA increased and TNFα mRNA decreased only with the ketogenic diet. Brain mtDNA levels fell in both the ketogenic and non-ketogenic high fat diet groups, although TOMM20 and COX4I1 protein levels were maintained, and mRNA and protein levels of the mtDNA-encoded COX2 subunit were also preserved. Overall, the pattern of changes observed in mice fed ketogenic and non-ketogenic high fat diets over a one month time period suggests these interventions enhance some aspects of the brain’s aerobic infrastructure, and may enhance mtDNA transcription efficiency. Further studies to determine which diet effects are due to changes in brain ketone body levels, fatty acid levels, glucose levels, altered brain insulin signaling, or other factors such as adipose tissue-associated hormones are indicated.

A bioenergetics systems evaluation of ketogenic diet liver effects

“…The ketogenic diet contained 7.2 kcal/g and the proportion of calories provided through that diet was 4.7% from protein, 93.4% from lard fat, and 1.8% from carbohydrate (BioServ #F3666). Ketosis in the ketogenic diet-fed mice was verified through measurements of serum β-hydroxybutyrate, which showed an approximate five-fold increase over that of the chow-fed mice (Selfridge et al 2015). …”

“…The mice we analyzed originally informed a study of how ketogenic diets affect brain bioenergetic infrastructures (Selfridge et al 2015). The report from that study documents select physiologic effects of the ketogenic diet intervention.…”

“…Details of the mice used in this study and their handling are provided in a prior manuscript (Selfridge et al 2015). Briefly, all animal procedures were approved by the University of Kansas Medical Center Animal Care and Use Committee, and we adhered to NIH guidelines for the proper treatment and use of laboratory animals.…”

Relationships Between Mitochondria and Neuroinflammation: Implications for Alzheimer's Disease

“…In this study, young adult C57Bl/6J mice were placed on a ketosis-inducing high-fat ketogenic diet, a non-ketosis inducing high fat Western diet, or a standard chow diet for one month [64]. Mice on the ketogenic diet experienced an approximate five-fold increase in their serum β-hydroxybutyrate level, while mice on the Western diet did not increase their serum β-hydroxybutyrate level.…”

New Therapeutics to Modulate Mitochondrial Function in Neurodegenerative Disorders

“…One such lifestyle intervention is diet. Brain energy metabolism, including mitochondrial function, is altered with the ketogenic diet in pre-clinical mouse models [44–46]. Caloric restriction alters energy pathways through activation of sirtuin 1 (SIRT1), which can initiate downstream mitochondrial biogenesis [47].…”