Caloric restriction augments brain glutamic acid decarboxylase-65 and -67 expression.
The ketogenic diet is a very low-carbohydrate, high-fat diet used to treat refractory epilepsy. We hypothesized that this diet may act by increasing expression of glutamic acid decarboxylase (GAD), the rate-limiting enzyme in gamma-aminobutyric acid (GABA) synthesis. Thus, we evaluated brain GAD levels in a well-established, seizure-suppressing, rodent model of the ketogenic diet. Because the diet is most effective when administered with a modest ( approximately 10%) calorie restriction, we studied three groups of animals: rats fed ad libitum standard rat chow (Ad lib-Std); calorie-restricted standard chow (CR-Std); and an isocaloric, calorie-restricted ketogenic diet (CR-Ket). We found that GAD67 mRNA was significantly increased in the inferior and superior colliculi and cerebellar cortex in both CR diet groups compared with control (e.g., by 45% in the superior colliculus and by 71% in the cerebellar cortex; P <.001). GAD65 mRNA was selectively increased in the superior colliculus and temporal cortex in both CR-Std and CR-Ket diet groups compared with ad lib controls. The only apparent CR-Ket-specific effect was a 30% increase in GAD67 mRNA in the striatum (P =.03). Enhanced GAD immunoreactivity was detected in parallel with the mRNA changes. These data clearly show that calorie restriction increases brain GAD65 and -67 expression in several brain regions, independent of ketogenic effects. These observations may explain why caloric restriction improves the efficacy of the ketogenic diet in treating epilepsy and suggest that diet modification might be useful in treatment of a number of brain disorders characterized by impaired GAD or GABA activity.
Cheng
Clara M
CM
Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892.
Hicks
Kristin
K
Wang
Jie
J
Eagles
Douglas A
DA
Bondy
Carolyn A
CA
D000818:Animals; D001921:Brain / Q000166:cytology / Q000201:enzymology*; D031204:Caloric Restriction; D004040:Dietary Carbohydrates / Q000009:adverse effects / Q000378:metabolism; D004041:Dietary Fats / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D004827:Epilepsy / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D005508:Food Deprivation / Q000502:physiology*; D005526:Food, Formulated; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D007662:Ketosis / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000166:cytology / Q000201:enzymology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000096:biosynthesis*
D004040:Dietary Carbohydrates; D004041:Dietary Fats; D007527:Isoenzymes; D012333:RNA, Messenger; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; C401141:glutamate decarboxylase 2