Mice fed a high-fat, low-carbohydrate ketogenic diet (KD) exhibit marked changes in hepatic metabolism and energy homeostasis. Here, we identify liver-derived fibroblast growth factor 21 (FGF21) as an endocrine regulator of the ketotic state. Hepatic expression and circulating levels of FGF21 are induced by both KD and fasting, are rapidly suppressed by refeeding, and are in large part downstream of PPARalpha. Importantly, adenoviral knockdown of hepatic FGF21 in KD-fed mice causes fatty liver, lipemia, and reduced serum ketones, due at least in part to altered expression of key genes governing lipid and ketone metabolism. Hence, induction of FGF21 in liver is required for the normal activation of hepatic lipid oxidation, triglyceride clearance, and ketogenesis induced by KD. These findings identify hepatic FGF21 as a critical regulator of lipid homeostasis and identify a physiological role for this hepatic hormone.
A high-fat, ketogenic diet induces a unique metabolic state in mice. Am J Physiol Endocrinol Metab 292: E1724 -E1739, 2007. First published February 13, 2007; doi:10.1152/ajpendo.00717.2006.-Ketogenic diets have been used as an approach to weight loss on the basis of the theoretical advantage of a low-carbohydrate, high-fat diet. To evaluate the physiological and metabolic effects of such diets on weight we studied mice consuming a very-low-carbohydrate, ketogenic diet (KD). This diet had profound effects on energy balance and gene expression. C57BL/6 mice animals were fed one of four diets: KD; a commonly used obesogenic high-fat, high-sucrose diet (HF); 66% caloric restriction (CR); and control chow (C). Mice on KD ate the same calories as mice on C and HF, but weight dropped and stabilized at 85% initial weight, similar to CR. This was consistent with increased energy expenditure seen in animals fed KD vs. those on C and CR. Microarray analysis of liver showed a unique pattern of gene expression in KD, with increased expression of genes in fatty acid oxidation pathways and reduction in lipid synthesis pathways. Animals made obese on HF and transitioned to KD lost all excess body weight, improved glucose tolerance, and increased energy expenditure. Analysis of key genes showed similar changes as those seen in lean animals placed directly on KD. Additionally, AMP kinase activity was increased, with a corresponding decrease in ACC activity. These data indicate that KD induces a unique metabolic state congruous with weight loss.liver; gene expression OVER THE PAST FEW DECADES the rates of obesity have risen substantially worldwide. Paradoxically, the increases in body weight, particularly in Western countries, occurred during a period of emphasis on diets low in fat as a means for avoiding weight gain. These dietary recommendations were based largely on the concept that high-fat diets were less satiating (39) and that reducing dietary fat reduced risk for cardiovascular disease by lowering circulating fat and cholesterol (5). As a result of the perceived failure of traditional dietary advice, attention shifted to alternative dietary regimes, including lowglycemic-index diets and very-low-carbohydrate ketogenic diets. Interest in these diets derives in part from the theoretical effects of dietary composition on energy expenditure. Although a small number of human studies have found such diets to be more effective in short-term weight loss and without adverse effects on glucose, insulin, lipids, or blood pressure (7,14,42,49,51), reports on metabolic effects remain inconclusive (8,38). Thus the precise effects of macronutrient diet composition on energy balance remain controversial.Studies of the physiological effects of dietary composition are intrinsically difficult in human populations because of problems achieving both compliance and accurate dietary reporting. Therefore, we developed a mouse model to examine the effect of diet composition on physiology, with particular reference to energy expenditure and metab...
Ghrelin, a novel 28 amino acid peptide found in hypothalamus and stomach, was recently identified as the endogenous ligand for the growth hormone secretagogue receptor (GHS-R). We have now found that both intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) administration of ghrelin in freely feeding rats stimulated food intake. The onset of increased feeding was rapid and after i.c.v. administration was sustained for 24 hours. Following i.c.v. administration of 3 nmol ghrelin, the duration and magnitude of the feeding stimulation was similar to that following 5 nmol neuropeptide Y (NPY). Plasma growth hormone (GH) concentration increased following both i.c.v. and i.p. administration of ghrelin. Release of adrenocorticotrophic hormone (ACTH) was stimulated and thyroid stimulating hormone (TSH) inhibited following i.c.v. administration of ghrelin. These data suggest a possible role for the newly identified endogenous hypothalamic peptide, ghrelin, in stimulation of feeding and growth hormone secretion.
The central nervous system and gut peptide neuromedin U (NMU) inhibits feeding after intracerebroventricular injection. This study explored the hypothalamic actions of NMU on feeding and the hypothalamo-pituitary-adrenal axis. Intraparaventricular nucleus (intra-PVN) NMU dose-dependently inhibited food intake, with a minimum effective dose of 0.1 nmol and a robust effect at 0.3 nmol. Feeding inhibition was mapped by NMU injection into eight hypothalamic areas. NMU (0.3 nmol) inhibited food intake in the PVN (0-1 h, 59 +/- 6.9% of the control value; P < 0.001) and arcuate nucleus (0-1 h, 76 +/- 10.4% of the control value; P < 0.05). Intra-PVN NMU markedly increased grooming and locomotor behavior and dose-dependently increased plasma ACTH (0.3 nmol NMU, 24.8 +/- 1.9 pg/ml; saline, 11.4 +/- 1.0; P < 0.001) and corticosterone (0.3 nmol NMU, 275.4 +/- 40.5 ng/ml; saline, 129.4 +/- 25.0; P < 0.01). Using hypothalamic explants in vitro, NMU stimulated CRH (100 nM NMU, 5.9 +/- 0.95 pmol/explant; basal, 3.8 +/- 0.39; P < 0.01) and arginine vasopressin release (100 nM NMU, 124.5 +/- 21.8 fmol/explant; basal, 74.5 +/- 7.6; P < 0.01). Leptin stimulated NMU release (141.9 +/- 20.4 fmol/explant; basal, 92.9 +/- 9.4; P < 0.01). Thus, we describe a novel role for NMU in the PVN to stimulate the hypothalamo-pituitary-adrenal axis and locomotor and grooming behavior and to inhibit feeding.
Badman MK, Kennedy AR, Adams AC, Pissios P, MaratosFlier E. A very low carbohydrate ketogenic diet improves glucose tolerance in ob/ob mice independently of weight loss. Am J Physiol Endocrinol Metab 297: E1197-E1204, 2009. First published September 8, 2009; doi:10.1152/ajpendo.00357.2009.-In mice of normal weight and with diet-induced obesity, a high-fat, low-carbohydrate ketogenic diet (KD) causes weight loss, reduced circulating glucose and lipids, and dramatic changes in hepatic gene expression. Many of the effects of KD are mediated by fibroblast growth factor 21 (FGF21). We tested the effects of KD feeding on ob/ob mice to determine if metabolic effects would occur in obesity secondarily to leptin deficiency. We evaluated the effect of prolonged KD feeding on weight, energy homeostasis, circulating metabolites, glucose homeostasis, and gene expression. Subsequently, we evaluated the effects of leptin and fasting on FGF21 expression in ob/ob mice. KD feeding of ob/ob mice normalized fasting glycemia and substantially reduced insulin and lipid levels in the absence of weight loss. KD feeding was associated with significant increases in lipid oxidative genes and reduced expression of lipid synthetic genes, including stearoyl-coenzyme A desaturase 1, but no change in expression of inflammatory markers. In chow-fed ob/ob mice, FGF21 mRNA was elevated 10-fold compared with wild-type animals, and no increase from this elevated baseline was seen with KD feeding. Administration of leptin to chow-fed ob/ob mice led to a 24-fold induction of FGF21. Fasting also induced hepatic FGF21 in ob/ob mice. Thus, KD feeding improved ob/ob mouse glucose homeostasis without weight loss or altered caloric intake. These data demonstrate that manipulation of dietary macronutrient composition can lead to marked improvements in metabolic profile of leptin-deficient obese mice in the absence of weight loss. obesity; glucose intolerance; fibroblast growth factor 21 RECENT HUMAN STUDIES have shown that ketogenic diets (KD) may be effective at inducing weight loss and improving glycemic status with no adverse consequences on lipid profiles (12,14,15,34). Furthermore, a number of studies have shown that low-carbohydrate and KD mediate improvements in glycemic status in individuals with type 2 diabetes (10,29,31,40). To better understand the mechanisms by which KD can exert favorable metabolic effects, we developed a mouse model of KD feeding (6,20). We have used this system to examine the physiological effects of KD in mice fed chow and with dietary-induced obesity (DIO). In both cases, KD feeding was associated with lower levels of glycemia and enhanced fat oxidation (20). KD feeding of DIO mice results in rapid weight loss and dramatic improvements in metabolic status (20). These changes are associated with a concerted program of changes in hepatic gene expression. Genes coding for enzymes responsible for lipid oxidation and ketogenic enzymes are increased with a concomitant decrease in lipid synthetic and glucocatabolic genes, includin...
SummaryCaloric restriction, leanness and decreased activity of insulin/insulin-like growth factor 1 (IGF-1) receptor signaling are associated with increased longevity in a wide range of organisms from Caenorhabditis elegans to humans. Fatspecific insulin receptor knock-out (FIRKO) mice represent an interesting dichotomy, with leanness and increased lifespan, despite normal or increased food intake. To determine the mechanisms by which a lack of insulin signaling in adipose tissue might exert this effect, we performed physiological and gene expression studies in FIRKO and control mice as they aged. At the whole body level, FIRKO mice demonstrated an increase in basal metabolic rate and respiratory exchange ratio. Analysis of gene expression in white adipose tissue (WAT) of FIRKO mice from 6 to 36 months of age revealed persistently high expression of the nuclear-encoded mitochondrial genes involved in glycolysis, tricarboxylic acid cycle, β β β β -oxidation and oxidative phosphorylation as compared to expression of the same genes in WAT from controls that showed a tendency to decline in expression with age. These changes in gene expression were correlated with increased cytochrome c and cytochrome c oxidase subunit IV at the protein level, increased citrate synthase activity, increased expression of peroxisome proliferator-activated receptor γ γ γ γ coactivator 1 α α α α (PGC-1 α α α α ) and PGC-1 β β β β , and an increase in mitochondrial DNA in WAT of FIRKO mice. Together, these data suggest that maintenance of mitochondrial activity and metabolic rates in adipose tissue may be important contributors to the increased lifespan of the FIRKO mouse.
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