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http://en.wikipedia.org/wiki/Messenger_RNA#Eukaryotic_mRNA_turnover 

MicroRNA (miRNA)

Main article: microRNA

MicroRNAs (miRNAs) are small RNAs that typically are partially complementary to sequences in

metazoan messenger RNAs.[16] Binding of a miRNA to a message can repress translation of that

message and accelerate poly(A) tail removal, thereby hastening mRNA degradation. The

mechanism of action of miRNAs is the subject of active research.[17]

Hastening - Be quick to do something.

GI MICROFLORA

http://www.textbookofbacteriology.net/normalflora.html

GASTRIC BYPASS

http://www.post-gazette.com/pg/10062/1039722-114.stm

Biosci Biotechnol Biochem. 2001 Nov;65(11):2565-8.

Changes of pyridine nucleotide levels during adipocyte differentiation of mouse 3T3-L1 cells.

Fukuwatari T, Doi M, Sugimoto E, Kawada T, Shibata K.

Source

Department of Life Style Studies, School of Human Cultures, The University of Shiga Prefecture, Hikone, Japan.

fukkie@shc.usp.ac.jp

AbstractThe levels of NAD and NADP were measured in 3T3-L1 cells during a differentiation from preadipocytes

to adipocytes. The cells were grown in the ordinary medium and differentiated in the medium by adding

dexamethasone, 1-methyl-3-isobutylxanthine, and insulin for 2 days, and then they were grown in the

medium by adding only insulin for another 8 days to accumulate fat. The levels of cellular NAD and NADP

increased abruptly with days after differentiation, and the levels of NAD and NADP reached maximum at day

7, and at day 10 the values were decreased compared with the maximum values. These results suggest thatexpression of the pyridine nucleotide biosynthesis genes is induced in the differentiation process.

PMID:11791736

 

http://en.wikipedia.org/wiki/Selfish_Brain_Theory

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The “Selfish Brain” theory describes the characteristic of the human brain to cover its own,

comparably high energy requirements with the utmost of priorities when regulating energy fluxes

in the organism. The brain behaves selfishly in this respect. The "Selfish brain" theory amongst

other things provides a possible explanation for the origin of obesity, the severe and pathological

form of overweight.

Investigative approach of the Selfish Brain theory

The brain performs many functions for the human organism. Most are of a cognitive nature or 

concern the regulation of the motor system. A previously lesser investigated aspect of brain

activity was the regulation of energy metabolism. The "Selfish Brain" theory shed new light on this

function. This theory states that the brain behaves selfishly by controlling energy fluxes in such a

way that it allocates energy to itself before the needs of the other organs are satisfied. The

internal energy consumption of the brain is very high. Although its mass constitutes only 2% of 

the entire body weight, it consumes 50% of the carbohydrates ingested over a 24 hour period.

This corresponds to 100 g of glucose per day, or half the daily requirement for a human being. A

30 year-old office worker with a body weight of 75 kg and a height of 1.85 m consumes approx.

200 g glucose per day.

Before now the scientific community assumed that the energy needs of the brain, the muscles

and the organs were all met in parallel. The hypothalamus, an area of the upper brainstem, was

thought to play a central role in regulating two feedback loops within narrow limits.

The "lipostatic theory" established by Gordon C Kennedy in 1953 describes the fat

deposition feedback system.[1][ page needed ] The hypothalamus receives signals from circulating

metabolic products or hormones about how much adipose tissue there is in the body as well

as its prevailing metabolic status. Using these signals the hypothalamus can adapt the

absorption of nutrients so that the body’s fat depots remain constant, i.e. a "lipostasis" is

achieved.

The "glucostatic theory" developed in the same year by Jean Mayer describes the blood

glucose feedback system.[2][ page needed ]According to this theory the hypothalamus controls the

absorption of nutrients via receptors that measure the glucose level in the blood. In this way acertain glucose concentration is set by adjusting the intake of nutrients. Interestingly enough,

Mayer also included the brain in his calculations. Although he considered that food intake

served to safeguard the energy homoeostasis of the central nervous system, he did imply

that the energy flux from the body to the brain was a passive process.

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On the basis of these theories a number of international research groups still position the origin of 

obesity in a disorder in one of the two above described feedback systems.

http://www.jlr.org/content/48/4/826.full.pdf 

Together, our results suggest that the reduction in intracellular lipid by constitutive

expression of UCP1 reflects a downregulation of fat synthesis rather than an upregulation

of fatty acid oxidation.—Si, Y., S. Palani, A. Jayaraman, and K. Lee. Effects of forced

uncoupling protein 1 expression in 3T3-L1 cells on mitochondrial function and lipid

metabolism. J. Lipid Res. 2007. 48: 826–836

http://en.wikipedia.org/wiki/Lactic_acidosis

When excess intracellular lactate is released into the blood, maintenance of electroneutrality

requires a cation (e.g. a proton) to be released as well. This can reduce blood pH. Glycolysis

coupled with lactate production is neutral in the sense that it does not produce excess protons.

However, pyruvate production does produce protons. Lactate production is buffered

intracellularly, e.g. the lactate-producing enzyme lactate dehydrogenase binds one proton per 

pyruvate molecule converted. When such buffer systems become saturated, cells will transport

lactate into the blood stream. Hypoxia certainly causes both buildup of lactate and acidification,

and lactate is therefore a good "marker" of hypoxia, but lactate itself is not the cause of low pH.[4]

Lactic acidosis sometimes occurs without hypoxia, for example in rare congenital disorders where

mitochondria do not function at full capacity. In such cases, when the body needs more energythan usual, for example during exercise or disease, mitochondria cannot match the cells' demand

for ATP, and lactic acidosis results.

http://www.nature.com/oby/journal/v11/n3/full/oby200364a.html

Anatomical and morphological examination of the subcutaneous adipose tissue depot

has led to the identification of two distinct compartments within the subcutaneous

anatomical region: a superficial layer of adipose tissue, evenly distributed under the

abdominal skin layer; and a deeper subcutaneous adipose tissue compartment,

located under the superficial adipose tissue layer (Figure 1) (11). These anatomically

distinct abdominal subcutaneous fat compartments are separated by a fascial plane

(termed superficial or subcutaneous fascia), which is circumferential and fuses with

the underlying muscle wall in radiating strands at particular anatomic locations

(11, 12). Important morphological differences have been observed between these

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two adipose tissue layers. Specifically, the fat lobules of the superficial layer are

tightly packed, whereas those of the deep layer are large, irregular, and less

organized (11).

Cross-sectional computed tomography scans of a lean woman (left) and an obese

woman (right) of the study. The subcutaneous fascia (A) was delineated using the

computer interface of the scanner, and the area of each compartment was quantified

(B). (C) physical characteristics of the women.

http://www.sciencedirect.com/science/article/pii/0167488985900783

Regular paper 

Glucocorticoid effects on membrane lipid mobilityduring differentiation of murine B lymphocytes

http://en.wikipedia.org/wiki/Glucocorticoid

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Metabolic

The name "glucocorticoid" derives from early observations that these hormones were involved

in glucose metabolism. In the fasted state, cortisol stimulates several processes that collectively

serve to increase and maintain normal concentrations of glucose in blood.

Metabolic effects:

Stimulation of  gluconeogenesis, in particular, in the liver : This pathway results in the

synthesis of glucose from non-hexose substrates such as amino acids and glycerol from

triglyceride breakdown, and is particularly important in carnivores and certain herbivores.

Enhancing the expression of enzymes involved in gluconeogenesis is probably the best-

known metabolic function of glucocorticoids.

Mobilization of amino acids from extrahepatic tissues: These serve as substrates

for  gluconeogenesis.

Inhibition of glucose uptake in muscle and adipose tissue: A mechanism to conserve

glucose.

Stimulation of  fat breakdown in adipose tissue: The fatty acids released by lipolysis are

used for production of energy in tissues like muscle, and the released glycerol provide

another substrate for gluconeogenesis.

Glucocorticoids have been shown to exert a number of rapid actions that are independent of the

regulations of gene transcription. Binding of corticosteroids to the glucocorticoid receptor (GR)

stimulates phosphatidylinositol 3-kinase and protein kinase AKT, leading to endothelial nitric

oxide synthase (eNOS) activation and nitric oxide-dependent vasorelaxation

http://www.medscape.com/viewarticle/500858_2

Glucocorticoids and Ceramide Synthesis

The discovery that glucocorticoids have a large and specific effect on sphingolipids derived from

studies addressing the theory that the broad scope of corticosteroid action was due to the ability

of different hormones to directly modify membrane lipids.[39] Specifically, the well-recognizedimportance of corticosteroids in protection against stress was considered to possibly relate to

membrane fluidity, which is involved in the adaptation of bacteria, fish, and hibernating animals to

extremes of heat and cold.[40] To investigate this possibility, investigators quantified the fatty acid,

phospholipid, and sphingolipid composition of membranes in various cell types incubated with

dexamethasone. Notably, the glucocorticoid increased membrane sphingomyelin in rat

epididymal fat cells.[41] Dexamethasone was subsequently shown to increase sphingomyelin levels

in HeLa cells[42] and human polymorphonuclear leukocytes,[17] ceramide levels in a murine B

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lymphoma cell line,[16] and sphingosine levels in 3T3-L1 preadipocytes.[43] In vivo, epididymal fat

cell ghosts isolated from adrenalectomized rats demonstrated decreased sphingomyelin levels,

which could be restored by the administration of dexamethasone.[44] By contrast, these

researchers detected no change in either the levels or fatty acid composition of phospholipids,

nor did they detect a change in cellular cholesterol levels.

Recent studies have investigated the mechanism by which glucocorticoids regulate sphingolipid

production. Dexamethasone increases the expression and/or activity of SPT[45] and neutral and

acidic forms of sphingomyelinase.[17,43,46,47] These observations are consistent with the established

roles of glucocorticoid receptors as transcription factors whose entry into the nucleus is regulated

by ligand binding. Interestingly, Cifone et al.[47] demonstrated that dexamethasone also acutely

stimulates ceramide accumulation (i.e., within 15 min of dexamethasone addition) in thymocytes

by activating acid sphingomyelinase.

 

http://www.nature.com/nrc/journal/v4/n8/fig_tab/nrc1411_F4.html

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Ceramide can be formed de novo (pink) or from hydrolysis of sphingomyelin (blue) or cerebrosides

(green). Conversely, ceramide can be phosphorylated by ceramide kinase121 to yield ceramide-1-

phosphate, or can serve as a substrate for the synthesis of sphingomyelin or glycolipids. Ceramide

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can be metabolized (orange) by ceramidases (CDases)122, 123, 124 to yield sphingosine, which in turn is

phosphorylated by sphingosine kinases (SKs) to generate sphingosine-1-phosphate (S1P). S1P can

be cleared by the action of specific phosphatases that regenerate sphingosine or by the action of a

lyase that cleaves S1P into ethanolamine-1-phosphate and a C16-fatty-aldehyde. C1PP, ceramide-1-

phosphate phosphatase; CRS, cerebrosidase; CK, ceramide kinase; CS, ceramide synthase; DAG,

diacylglycerol; DES, dihydroceramide desaturase; GCS, glucosylceramide synthase; PC,

phosphatidylcholine; S1PP, S1P phosphatase; SMS, sphingomyelin synthase; SMase,

spingomyelinase; SPT, serine palmitoyl transferase.

Agonist-induced activation of sphingosine kinase 1 (SK1) — for example, by tumour-necrosis factor-

α (TNFα) — involves its interaction with TNF-associated factor 2 (TRAF2)68 and phosphorylation by

extracellular-regulated kinase 1 (ERK1) or ERK2 (Ref. 127), which then induces translocation of the

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enzyme from the cytoplasm to the plasma membrane127, leading to increased generation of 

sphingosine-1-phosphate (S1P) from sphingosine (SPH). S1P functions as a specific ligand for the

G-protein-coupled S1P receptors. S1P receptors couple to various G proteins, such that S1P can

mediate distinct biological responses based on the relative expression levels of S1P receptors and

specific G proteins128. Primarily, S1P-mediated pathways are proliferative, pro-inflammatory

(through cyclooxygenase 2 (COX2)) and anti-apoptotic (through inhibition of the pro-apoptotic

proteins caspase-3 and BAX). NF-κB, nuclear factor-κB. TNFR1, tumour-necrosis factor receptor 1.

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Schematic diagram depicting the metabolic pathways regulating ceramide degradation and

metabolism.

http://ehp.niehs.nih.gov/members/2001/suppl-2/283-289merrill/merrill-full.html

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http://www.hindawi.com/journals/drp/2010/702409/fig2/

Figure 2: Sphingomyelin synthase. The reaction catalyzed by sphingomyelin synthase

(SM synthase) results in a reduction in ceramide and an increase in diacylglycerol and

sphingomyelin levels. The reported phosphatidylcholine-specific phospholipase C inhibitor D609 also inhibits sphingomyelin synthase activity.

Annu Rev Nutr. 1999;19:463-84.

Regulation of fatty acid oxidation in skeletal muscle.

Rasmussen BB, Wolfe RR.

Source

Metabolism Unit, Shriners Burns Institute, Texas, USA. brasmuss@sbi.utmb.edu

AbstractResearchers using animals are beginning to elucidate the control of fatty acid metabolism in muscle at the

molecular and enzymatic level. This review examines the physiological data that has been collected from

human subjects in the context of the proposed control mechanisms. A number of factors, including the

availability of free fatty acids and the abundance of fatty acid transporters, may influence the rate of muscle

fatty acid oxidation. However, the predominant point of control appears to be the rate at which fatty acyl-

coenzyme A is transported into the mitochondria by the carnitine palmitoyl transferase system. In turn,

evidence suggests that the intracellular concentration of malonyl-coenzyme A in muscle is an important

regulator of carnitine palmitoyl transferase-I activity. Malonyl-coenzyme A is increased by glucose, which is

likely the mechanism whereby glucose intake suppresses the transfer of fatty acids into the mitochondria for 

subsequent oxidation. In contrast, malonyl-coenzyme A levels decrease during exercise, which enables

increased fatty acid oxidation. However, for any given carnitine palmitoyl transferase-I activity, there may be

an effect of free fatty acid availability on fatty acid oxidation, particularly at low levels of free fatty acids.

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Nonetheless, the rate of glucose or glycogen metabolism is probably the primary regulator of the balance

between glucose and fatty acid oxidation in muscle.

http://en.wikipedia.org/wiki/Malonyl-CoA

Regulation

Malonyl-CoA is a highly-regulated molecule in fatty acid synthesis; as such, it inhibits the rate-

limiting step in beta-oxidation of fatty acids. Malonyl CoA inhibits fatty acids from associating

with carnitine, thereby preventing them from entering the mitochondria where fatty acid

oxidation and degradation occur.

http://www.nature.com/nrd/journal/v3/n4/fig_tab/nrd1344_ft.html

AMP kinase and malonyl-CoA: targets for therapy of the metabolic syndrome

Neil Ruderman & Marc Prentki

Nature Reviews Drug Discovery 3, 340-351 (April 2004)

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By inhibiting CPT1, malonyl-CoA, which is derived from glucose, diminishes FA-CoA entrance into

mitochondria where they are oxidized, thereby making more cytosolic FA-CoA available for TG, DAG

and ceramide synthesis and possibly for lipid peroxidation. AMPK could inhibit these events and

increase fatty acid oxidation, acutely by phosphorylating or otherwise inhibiting ACC and GPAT and

activating MCD, and chronically by diminishing the expression of SREBP1c and activating PGC1 and

PPAR (not shown). The basis for its ability to diminish oxidant stress is not known. Whether AMPK

activation results in enhancement or inhibition of a process is denoted in the figure by plus and

minus signs, respectively. ROS, reactive oxygen species.

Download file

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Regulation of ACC and, secondarily, the concentration of malonyl-CoA by AMPK and cytosolic citrate.

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AMPK activation, such as occurs in many tissues during exercise or glucose deprivation,

phosphorylates ACC and inhibits its activity. Conversely, a sustained excess of glucose, and possibly

inactivity, decrease AMPK phosphorylation and activity and cause ACC activation. In muscle, the

pancreatic -cell, and probably in other cells, glucose availability also determines the concentration

of cytosolic citrate, an allosteric activator of ACC and a precursor of its substrate, cytosolic acetyl-

CoA. Such changes in citrate occur rapidly (min) and may be responsible for early changes in

malonyl-CoA concentration and for sustained changes in malonyl-CoA under conditions in which

assayable AMPK activity is not altered. ACC, acetyl-CoA carboxylase; AMPK, AMP kinase.

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Endotoxin

Chemotherapeutic agents

1,25 dihydroxy vitamin D

gamma interferon

heat

ionizing radiation [1][10]

Ceramidase Inhibitors

It is interesting to note that the substances that can cause ceramide to be generated tend to be

stress signals that can cause the cells to go into programmed cell death. Ceramide thus acts as

an intermediary signal that connects the external signal to the internal metabolism of the cells.

http://diabetes.diabetesjournals.org/content/58/2/337.abstract

Plasma Ceramides Are Elevated in ObeseSubjects With Type 2 Diabetes andCorrelate With the Severity of InsulinResistance

Plasma ceramide levels are elevated in type 2 diabetic subjects and may contributeto insulin resistance through activation of inflammatory mediators, such as TNF-α.

http://www.ncbi.nlm.nih.gov/pubmed/21437908

J Cell Physiol. 2011 Mar 24. doi: 10.1002/jcp.22745. [Epub ahead of print]

Ceramide metabolism is affected by obesity and diabetes in humanadipose tissue.

ceramide (Cer), dihydroceramide (dhCer), sphingosine, sphinganine (SPA), sphingosine-1-phosphate(pmol/mg of protein), the expression (mRNA) and activity of key enzymes responsible for Cer metabolism:serine palmitoyltransferase (SPT), neutral and acidic sphingomyelinase (n-, aSMase) and neutral and acidicceramidase (n -, aCDase) were examined in human adipose tissue.

The expression of examined enzymes was elevated in both obese groups. The SPT and CDases activityincreased whereas aSMase activity deceased in both obese groups.

We have found correlation between adipose tissue ceramide content and plasma adiponectin concentration(r=0.69, p< 0.001) and negative correlation between total ceramide content and HOMA-IR index(homeostasis model of insulin resistance) (r = -0.67, p< 0.001).

The contents of SPA and Cer were significantly lower whereas the content of dhCer was higher in bothobese groups than the respective values in the lean subjects.

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We have found that both obesity and diabetes affected pathways of sphingolipid metabolism in the adiposetissue.

http://www.cerrx.com/approach.php

http://birzeit.academia.edu/JohnnyStiban/Papers/99657/Dihydroceramide_hinders_ceram

ide_channel_formation_Implications_on_apoptosis

dihydro ceramide blocks channel formation

http://www.jbc.org/content/277/29/25847.full

The Ceramide-centric Universe of Lipid-mediated Cell Regulation: StressEncounters of the Lipid Kind

 The Journal of Biological Chemistry, 277,25847-25850

The Mitochondrion: a Novel Compartment for CeramideMetabolism and ActionA novel CDase has been localized to mitochondria, demonstrating unequivocally theexistence of a mitochondrial pathway of ceramide metabolism (22). Ceramide levelshave been detected in mitochondria (23), and TNF was shown to induce

accumulation of ceramide in the heavy membrane compartment (10,000 × gpellet)(24). The addition of exogenous ceramide to purified mitochondria results ininhibition of the respiratory chain, the generation of reactive oxygen species, and therelease of cytochrome c(24-27). The expression of bacterial SMase in mitochondria,but not other subcellular compartments, resulted in induction of apoptosis (28),suggesting a role for endogenous mitochondrial ceramide in regulating apoptosis.

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Key Enzymes of Ceramide Metabolism as Switches in CellRegulationBecause of the intimate interconnections of lipid metabolism, many of the enzymes that regulate bioactive lipids also function as switches byregulating the levels of bioactive substrates and products. For

example, ceramidases can regulate the levels of ceramide (substrate)and/or sphingosine and S1P (products), with S1P often exerting anti-apoptotic effects that antagonize ceramide-mediated responses (seeminireview by Spiegel and Milstien (58)). TNF has been shown toactivate CDases, and this was correlated with lack of accumulation of ceramide and absence of an apoptotic response. Also, the action of IL-1 was shown to induce activation of CDase especially at lowconcentrations of the cytokine, thus leading to sphingosine-mediatedresponses. At higher concentrations of IL-1, ceramide accumulates andmediates effects of IL-1 on expression of α1-acid glycoprotein (2). SMsynthase (or inositol phosphoceramide synthase in yeast) regulates the

levels of ceramide and DAG in a reciprocal manner. Indeed, evidencehas been provided that active SM synthase can switch a signalingresponse from one mediated by ceramide (inhibition of NF-κB) to onemediated by DAG (activation of NF-κB) (49). Thus, many of theenzymes of sphingolipid metabolism are emerging as regulatedswitches controlling the relative levels of more than one bioactive lipid.

Figure 1Basic pathways of ceramide metabolism and interrelationship of regulatorypathways mediated by bioactive lipids. Ceramide can be formed de novo orfrom hydrolysis of SM or complex glycolipids (horizontal plane in diagram). In turn,ceramide may be converted to sphingosine (Sph) or serve as a substrate for SM

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synthesis (generating DAG) or glycolipids. Each of the major bioactive lipids is thencapable of interacting with specific targets leading to specific responses (verticalplane). PalCoA, palmitoyl-CoA;DHS, dihydrosphingosine; DHCer , dihydroceramide;SK ,sphingosine kinase; PC, phosphatidylcholine;PA, phosphatidic acid; SMS, SMsynthase;DGK , DAG kinase; SL, sphingolipid.

Figure 2Compartmentalization of ceramide metabolism and function. Shown areseveral distinct compartments of ceramide metabolism and function (refer to text fordiscussion). Cer , ceramide; DHS, dihydrosphingosine; Cath D, cathepsin D; Sph,sphingosine; Sph-K , sphingosine kinase; Alk , alkaline;PalCoA, palmitoyl-CoA;SR,sarcoplasmic reticulum; dhCer , dihydroceramide;CerS, ceramide synthase; deSat ,desaturase; PC, phosphatidylcholine; SMS, SM synthase.

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Similarly, little is known concerning SM synthase, one of the most recalcitrantenzymes that has resisted efforts at purification and cloning.

http://www.ncbi.nlm.nih.gov/pubmed/21669879

J Biol Chem. 2011 Jun 13. [Epub ahead of print]

Dynamic modification of sphingomyelin in lipid microdomains controlsdevelopment of obesity, fatty liver, and type 2 diabetes.

Lipid microdomains or caveolae, small invaginations of plasma membrane, have emerged as importantelement for lipid uptake and glucose homeostasis. Sphingomyelin (SM) is one of the major phospholipids of the lipid microdomains. In this study, we investigated the physiological function of sphingomyelinsynthase 2 (SMS2) using SMS2-knockout mice, and found that SMS2 deficiency prevents high fat diet-induced obesity and insulin resistance. Interestingly, in the liver of SMS2-knockout mice, large and maturedlipid droplets were scarcely observed. Treatment with siRNA for SMS2 also decreased the large lipiddroplets in HepG2 cells. Additionally, the siRNA of SMS2 decreased the accumulation of triglyceride in liver of leptin-deficient (ob/ob) mice, strongly suggesting that SMS2 is involved in lipid droplets formation.Furthermore, we found that SMS2 exists in lipid microdomains and partially associates with the fatty acidtransporter CD36/FAT and with caveolin 1, a scaffolding protein of caveolae. Since CD36/FAT and caveolin1 exist in lipid microdomains and are coordinately involved in lipid droplets formation, SMS2 is implicated inmodulation of the SM in lipid microdomains, resulting in the regulation of CD36/FAT and caveolae. Here, weestablished new cell lines, in which we can completely distinguish SMS2 activity from SMS1 activity, and wedemonstrated that SMS2 could convert ceramide produced in the outer leaflet of the plasma membrane intoSM. Our findings demonstrate the novel and dynamic regulation of lipid microdomains via conformationalchanges in lipids on the plasma membrane by SMS2, which is responsible for obesity and type 2 diabetes.

http://www.nutridesk.com.au/chili.phtml

http://www.jbc.org/content/283/31/21418.full.pdf 

Capsaicin Stimulates Uncoupled ATP Hydrolysis by the

Sarcoplasmic Reticulum Calcium Pump

In muscle cells the sarcoplasmic reticulum (SR) Ca 2+-ATPase (SERCA) couples thefree energy of ATP hydrolysis to pump Ca 2+ ions from the cytoplasm to the SR lumen.

In addition, SERCA plays a key role in non-shivering thermogenesis through uncoupled

reactions, where ATP hydrolysis takes place without active Ca 2+ translocation.

Capsaicin (CPS) is a naturally occurring vanilloid, the consumption of which is linked

with increased metabolic rate and core body temperature.

To the best of our knowledge CPS is the first natural drug that augments uncoupled

SERCA, presumably resulting in thermogenesis. The role of CPS as a SERCA modulator 

is discussed.

Phytother Res. 2011 Jun;25(6):935-9. doi: 10.1002/ptr.3339. Epub 2010 Nov 17.

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Effects of Capsaicin on Lipid Catabolism in 3T3-L1 Adipocytes.

Lee MS, Kim CT, Kim IH, Kim Y.

Source

Department of Nutritional Science and Food Management, Ewha Womans University, Seoul, 120-750, Korea.

AbstractCapsaicin (8-methyl-N-vanillyl-6-nonenamide) is a pungent ingredient of red peppers, and has been

reported to reduce body weight gain and adiposity in rodents. The present study investigated the effects of 

capsaicin on lipid catabolism in differentiated 3T3-L1 adipocytes. Capsaicin decreased the intracellular lipid

content in a concentration-dependent manner. The release of glycerol into the medium was increased by the

addition of capsaicin. The mRNA levels of genes involved in lipid catabolism such as hormone sensitive

lipase (HSL), carnitine palmitoyl transferase-Iα (CPTI-α) and uncoupling protein 2 (UCP2) were up-regulated

significantly. These results suggest that capsaicin exerts its lipolytic action by increasing the hydrolysis of 

triacylglycerol in adipocytes, and that these effects are mediated at least partially by regulation of the

expression of multiple genes that are involved in the lipid catabolic pathway, such as HSL and CPT-Iα, and

those involved in thermogenesis such as UCP2. Copyright © 2010 John Wiley & Sons, Ltd.

http://en.wikipedia.org/wiki/Capsaicin

http://jap.physiology.org/content/95/6/2408.full

CAPSICUM FRUITS, red peppers, are used throughout the world as spices that stimulate

gustation and make insipid foods more appetizing. The major pungent principle of red pepper is capsaicin (36), which has been reported to elevate body temperature

(11), stimulate the secretion of catecholamines (52), promote energy expenditure

(24), and suppress body-fat accumulation (23) in experimental animals.

Consequently, capsaicin is thought to constitute a potential dietetic therapy for

obesity and diabetes. However, capsaicin is strongly pungent and neurotoxic (22),

which largely prohibits its administration to humans.

http://en.wikipedia.org/wiki/Oleic_acid

Triglyceride esters of oleic acid compose the majority of olive oil, although there may be less than

2.0% as free acid in the virgin olive oil, with higher concentrations making the olive oil inedible. It

also makes up 59-75% of  pecan oil,[3] 36-67% of peanut oil,[4] 15-20% of grape seed oil, sea

buckthorn oil, and sesame oil,[2] and 14% of poppyseed oil.[5] It is abundantly present in many

animal fats, constituting 37 to 56% of chicken and turkey fat,[6] and 44 to 47% of lard, etc.

Oleic acid is the most abundant fatty acid in human adipose tissue.

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Fatty acids as natural uncouplers preventing generationof  and H2O2 by mitochondria in the resting state

Both natural (laurate) and artificial (m-chlorocarbonylcyanide phenylhydrazone; CCCP) uncouplers strongly

inhibit and H2O2 formation by rat heart mitochondria oxidizing succinate. Carboxyatractylate, an

ATP/ADP antiporter inhibitor, abolishes the laurate inhibition, the CCCP inhibition being unaffected.Atractylate partially releases the inhibition by laurate and decelerates the releasing effect of carboxyatractylate. GDP is much less effective than carboxyatractylate in releasing the laurate inhibition of reactive oxygen species (ROS) formation. Micromolar laurate concentrations arresting the ROS formationcause strong inhibition of reverse electron transfer from succinate to NAD+, whereas State 4 respiration andthe transmembrane electric potential difference (ΔΨ) level are affected only slightly. It is suggested that (i)free fatty acids operate as natural ‘mild uncouplers' preventing the transmembrane electrochemical

H+potential difference ( ) from being above a threshold critical for ROS formation by complex I and,to a lesser degree, by complex III of the respiratory chain, and (ii) it is the ATP/ADP-antiporter, rather thanuncoupling protein 2, that is mainly involved in this antioxidant mechanism of heart muscle mitochondria.

http://en.wikipedia.org/wiki/Sodium-glucose_transport_proteins

Sodium-dependent glucose cotransporters are a family of glucose transporter  found in the

intestinal mucosa of the small intestine (SGLT1) and the proximal tubule of the nephron (SGLT2

in PCT and SGLT1 in PST). They contribute to renal glucose reabsorption. In the kidneys, 100%

of the filtered glucose in the glomerulus has to be reabsorbed along the nephron (98% in PCT,

via SGLT2). In case of too high plasma glucose concentration (hyperglycemia), glucose is

excreted in urine (glucosuria); because SGLT are saturated with the filtered monosaccharide.

One must know that glucose is never secreted by the nephron.

http://en.wikipedia.org/wiki/Dapagliflozin

Dapagliflozin inhibits subtype 2 of the sodium-glucose transport proteins (SGLT2), which is

responsible for at least 90% of the glucose reabsorption in the kidney. Blocking this transporter 

causes blood glucose to be eliminated through the urine.[4]

Selectivity 

The IC50 for SGLT2 is less than one thousandth of the IC50 for SGLT1 (1.1 versus 1390 nmol/l), so

that the drug does not interfere with the intestinal glucose absorption

http://www.medscape.com/viewarticle/724336