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...

During the past decade, chirally autocatalytic systems that exhibit unusual and interesting phenomena, such as spontaneous chiral symmetry breaking and stochastic behavior, have been identified. In this Account we outline the context in which chiral autocatalysis is of interest, summarize recent advances, and discuss our current understanding of the underlying kinetics and mechanisms. In addition, we note some fundamental aspects of amplification of enantiomeric excess and sensitivity of symmetry breaking transitions to asymmetric factors.

Amyloid /3

AMP-activated protein kinase (AMPK) is a key regulator of cellular energy balance and of the effects of leptin on food intake and fatty acid oxidation. Obesity is usually associated with resistance to the effects of leptin on food intake and body weight. To determine whether diet-induced obesity (DIO) impairs the AMPK response to leptin in muscle and/or hypothalamus, we fed FVB mice a high fat (55%) diet for 10 -12 weeks. Leptin acutely decreased food intake by ϳ30% in chow-fed mice. DIO mice tended to eat less, and leptin had no effect on food intake. Leptin decreased respiratory exchange ratio in chow-fed mice indicating increased fatty acid oxidation. Respiratory exchange ratio was low basally in high fat-fed mice, and leptin had no further effect. Leptin (3 mg/kg intraperitoneally) increased ␣2-AMPK activity 2-fold in muscle in chow-fed mice but not in DIO mice. Leptin decreased acetyl-CoA carboxylase activity 40% in muscle from chow-fed mice. In muscle from DIO mice, acetyl-CoA carboxylase activity was basally low, and leptin had no further effect. In paraventricular, arcuate, and medial hypothalamus of chow-fed mice, leptin inhibited ␣2-AMPK activity but not in DIO mice. In addition, leptin increased STAT3 phosphorylation 2-fold in arcuate of chow-fed mice, but this effect was attenuated because of elevated basal STAT3 phosphorylation in DIO mice. Thus, DIO in FVB mice alters ␣2-AMPK in muscle and hypothalamus and STAT3 in hypothalamus and impairs further effects of leptin on these signaling pathways. Defective responses of AMPK to leptin may contribute to resistance to leptin action on food intake and energy expenditure in obese states.

Since the model proposed by Frank (Frank FC, Biochem Biophys Acta 1953;11:459-463), several alternative models have been developed to explain how an asymmetric non-racemic steady state can be reached by a chirally symmetric chemical reactive system. This paper explains how a stable non-racemic regime can be obtained as a symmetry breaking occurring in a far-from-equilibrium reactive system initiated with an initial imbalance. Departing from the variations around the original Frank's model that are commonly described in the literature, i.e. open-flow systems of direct autocatalytic reactions, we discuss recent developments emphasizing both an active recycling of components and an autocatalytic network of simple reactions. We will present our APED model as the most natural realization of such thermodynamic openness and non-equilibrium, of recycling and of network autocatalysis, each of these in prebiotic conditions. The different experimental and theoretical models in the literature will be classified according to mechanism. The place and role of such self-structured networks responsible for the presence of homochirality in the primitive Earth will be detailed.

As a supercooled melt at 150 °C, the chiral compound 1,1‘-binaphthyl racemizes rapidly. The melt solidifies as a conglomerate of crystals, each consisting exclusively of either R-(−)- or S-(+)-enantiomer. We find that crystallization performed with a 2.00 g sample with constant stirring produces a large enantiomeric excess (mean 77%) in almost every crystallization. The predominance of R-(−) or S-(+) was random. Unstirred 2.00 g samples of binaphthyl produce a much lower enantiomeric excess (mean 20%) with optical activity centered around zero similar to an earlier report. Thus, chiral symmetry breaking can be realized in crystallization from a melt by the mere act of stirring, as it can be in crystallization from a solution.

Expression of group IIA secretory phospholipase A 2 (sPLA 2 -IIA) is documented in the cerebral cortex (CTX) after ischemia, suggesting that sPLA 2 -IIA is associated with neurodegeneration. However, how sPLA 2 -IIA is involved in the neurodegeneration remains obscure. To clarify the pathologic role of sPLA 2 -IIA, we examined its neurotoxicity in rats that had the middle cerebral artery occluded and in primary cultures of cortical neurons. After occlusion, sPLA 2 activity was increased in the CTX. An sPLA 2 inhibitor, indoxam, significantly ameliorated not only the elevated activity of the sPLA 2 but also the neurodegeneration in the CTX. The neuroprotective effect of indoxam was observed even when it was administered after occlusion. In primary cultures, sPLA 2 -IIA caused marked neuronal cell death. Morphologic and ultrastructural characteristics of neuronal cell death by sPLA 2 -IIA were apoptotic, as evidenced by condensed chromatin and fragmented DNA. Before apoptosis, sPLA 2 -IIA liberated arachidonic acid (AA) and generated prostaglandin D 2 (PGD 2 ), an AA metabolite, from neurons. Indoxam significantly suppressed not only AA release, but also PGD 2 generation. Indoxam prevented neurons from sPLA 2 -IIA-induced neuronal cell death. The neuroprotective effect of indoxam was observed even when it was administered after sPLA 2 -IIA treatment. Furthermore, a cyclooxygenase-2 inhibitor significantly prevented neurons from sPLA 2 -IIA-induced PGD 2 generation and neuronal cell death. In conclusion, sPLA 2 -IIA induces neuronal cell death via apoptosis, which might be associated with AA metabolites, especially PGD 2 . Furthermore, sPLA 2 contributes to neurodegeneration in the ischemic brain, highlighting the therapeutic potential of sPLA 2 -IIA inhibitors for stroke.

AMP-activated protein kinase (AMPK), an evolutionarily conserved serine-threonine kinase that senses cellular energy status, is activated by stress and neurohumoral stimuli. We investigated the mechanisms by which adrenergic signaling alters AMPK activation in vivo. Brown adipose tissue (BAT) is highly enriched in sympathetic innervation, which is critical for regulation of energy homeostasis. We performed unilateral denervation of BAT in wild type (WT) mice to abolish neural input. Six days post-denervation, UCP-1 protein levels and AMPK ␣2 protein and activity were reduced by 45%. In ␤ 1,2,3 -adrenergic receptor knock-out mice, unilateral denervation led to a 25-45% decrease in AMPK activity, protein expression, and Thr 172 phosphorylation. In contrast, acute ␣-or ␤-adrenergic blockade in WT mice resulted in increased AMPK ␣ Thr 172 phosphorylation and AMPK ␣1 and ␣2 activity in BAT. But short term blockade of ␣-adrenergic signaling in ␤ 1,2,3 -adrenergic receptor knock-out mice resulted in decreased AMPK activity in BAT, which strongly correlated with enhanced phosphorylation of AMPK on Ser 485/491 , a site associated with inhibition of AMPK activity. Both PKA and AKT inhibitors attenuated AMPK Ser 485/491 phosphorylation resulting from ␣-adrenergic blockade and prevented decreases in AMPK activity. In vitro mechanistic studies in BAT explants showed that the effects of ␣-adrenergic blockade appeared to be secondary to inhibition of oxygen consumption. In conclusion, adrenergic pathways regulate AMPK activity in vivo acutely via alterations in Thr 172 phosphorylation and chronically through changes in the ␣ catalytic subunit protein levels. Furthermore, AMPK ␣ Ser 485/491 phosphorylation may be a novel mechanism to inhibit AMPK activity in vivo and alter its biological effects. AMP-activated protein kinase (AMPK),4 an evolutionarily conserved serine threonine kinase, is a fuel-sensing enzyme complex activated by cellular stresses that increase AMP or deplete ATP including hypoxia, ischemia, glucose deprivation, uncouplers of oxidative phosphorylation, exercise, and muscle contraction (1, 2). Once activated, AMPK phosphorylates multiple downstream substrates that function to preserve the AMP: ATP ratio through inhibition of ATP-catabolizing pathways and promotion of ATP-generating pathways. Mechanisms involved in AMPK activation include 1) binding of AMP to an allosteric site on the ␥ subunit, which renders the holoenzyme resistant to inactivating serine phosphatases and may also have direct allosteric effects on kinase activity (1, 2) and 2) phosphorylation by upstream AMPK kinases of the ␣ (catalytic) subunits on Thr 172 , which is essential for kinase activity. Recent studies employing INS-1 cells (3), hepatitis C virus harboring replicon cells (4), and isolated heart preparations (5) have demonstrated another potential regulatory mechanism; that is, AMPK may also undergo inhibitory phosphorylation on serine 485 and 491 residues of the ␣1 and ␣2 catalytic subunits, respectively. Some data suggest that upstr...