Fat cell lipolysis control

Bezaire and Langin have produced a very good review of the hormonal regulation of adipocyte lipolysis
White adipose tissue is an unlimited pool of energy. In White adipose tissue non esterified fatty acids originating from dietary intake or de novo synthesis are stored as triacylglycerides in highly-structured hydrophobic lipid droplets (LD). As a consequence of its its storage capacity and ability to hydrolyse triacylglycerides (a process termed lipolysis) White adipose tissue provides a non esterified fatty acids buffering system for other organs. Lipolysis is the breakdown of one triacylglyceride molecule to three energy-rich non esterified fatty acids and one glycerol molecule, which are released into the bloodstream and are available for uptake by other tissues. non esterified fatty acids are not only an energy source, they are also signalling molecules. An excess of non esterified fatty acids can interfere with normal metabolism, which happens in obesity and type 2 diabetes. Chronically increased non esterified fatty acids alter glucose and lipid metabolism in skeletal muscle and liver and may lead to insulin resistance
Tight regulatory control of lipolysis is provided by cateholamines and insulin. Adrenaline and the neurotransmitter noradrenaline stimulate lipolysis through the activation of β1- and β2-adrenergic receptors. Coupling of β1- and β2- adrenergic receptors to stimulatory GTP-binding protein receptors activate adenylyl cyclase, increasing cAMP production. A rise in cAMP activates protein kinase A, "which phosphorylates hormone sensitive lipase and LD-coating protein perilipin to stimulate lipolysis. Conversely, catecholarnines can inhibit lipolysis through the activation of α2-AR and their coupling to inhibitory GTP binding protein receptors. The latter inhibit adenylyl cyclase action and cAMP production. Thus, - adrenergic receptors -dependent lipolysis is dictated by the combined effects of pro-lipolytic β-adrenergic receptors and anti-lipolytic α2- adrenergic receptors. Impairment in protein kinase A-stirnulated lipolysis observed in obesity is thought to result from increased stimulation of α-2 - adrenergic receptors. Insulin also regulates lipolysis when binding to its receptor on adipocytes. Insulin binding to insulin receptor substrate 1 leads to phosphodiesterase 3B activation, which degrades cAMP, and consequently reduces PKA activation. Thus, in a postprandial state insulin not
only favours substrate uptake and storage but also minimizes triacylglyceride breakdown in adipocytes.
In human fat cells an additional signal transduction pathway, independent of catecholamines and insulin, is implicated in pro-lipolytic events. Natriuretic peptides bind type A receptors, which possess intrinsic guanylyl cyclase activity . Increases in cGMP activate Protein Kinase G, which similarly to Protein Kinase A phosphorylates hormone sensitive lipase and protein perilipin . Stimulation of lipolysis by natriuretic peptides is of similar magnitude to that of catecholarnines and is particularly pronounced during exercise.
Natriuretic peptides, catecholamines and insulin provide the main regulatory control of lipolysis in human adipocytes. Additional hormones and factors such as growth hormone, TNFa, and IL-6 also influence lipolysis by altering the signalling pathways or lipolytic machinery. There is also a wealth of anti-lipolytic systems activated by catecholamines, adenosine, PG and metabolites for which the physiological relevance is still unknown.
Bezaire and Langin 2009 Regulation of adipose tissue biology. Proceedings of the Nutrition Society vol 68 pp 350-360

Adipose tissue

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This is such an interesting paper on a most important topic, adipose tissue. All mammals are provided with two distinct adipose cells, white and brown adipocytes. White adipocytes store lipids to provide fuel to the organism, allowing intervals between meals. Brown adipocytes use lipids to produce heat. Previous descriptions have placed these tissues in distinct sites of the body; however, it has been demonstrated that they are present together in many depots, which has led to the new concept of the adipose organ. In order to explain their coexistence tbe hypothesis of reversible physiological transdifferentiation has been developed, i.e. they are contained together because they are able to convert, one into the other. In effect, if needed the brown component of the organ could increase at the expense of the white component and vice versa. This plasticity is important because the brown phenotype of the organ is associated witb resistance to obesity and its related disorders. A new example of reversible physiological transdifferentiation of adipocytes is offered by the mammary gland during pregnancy, lactation and post-lactation stages. The gravidic hormonal stimulus seems to trigger a transdifferentiation of adipocytes into milk-producing and secreting epithelial glands. In the post-lactation period some of the epithelial cells of the mammary gland seem to transdifferentiate into adipocytes. Recent unpublished results suggest that explanted adipose tissue, as well as explanted isolated mature adipocytes, is able to transdifferentiate into glands with epithelial markers of milk-secreting mammary glands.

Cinti (2009) Reversible physiological transdifferentiation in the adipose organ . Proceedings of the Nutrition Society vol 68 pp340-349

one carbon folate genetics

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Genetic polymorphisms in the one-carbon folate pathway have been widely studied in association with a number of conditions. Most of the research has focused on the 677C>T polymorphism in the coding region of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene.
However, there are a total of 25 genes in this pathway coding for enzymes, transporters and receptors, which can be investigated using 267 tagging single nucleotide polymorphisms (SNPs); using SNP database (dbSNP), 38 non-synonymous SNPs with a minor allele frequency of >5% are present in these genes. Most of these variants have not been investigated in relation to disease or drug response phenotypes. In addition, their functional consequences are largely unknown.

Prediction of the functional effect using six publicly available programs (PolyPhen, SIFT BLink, PMut, SNPs3D, I-Mutant2.0 and LS-SNP) was limited to functionally well-characterized SNPs such as MTHFR c.677C>T and c.1298A>C ranking low. Epigenetic modifications may also be important with some of these genes.

Investigation of the one-carbon folate pathway genes has been limited.

Carret al 2009 Investigation of inter-individual variability of the one-carbon folate pathway: a bioinformatic and genetic review The Pharmacogenomics Journal (2009) 9, 291–305;

obesity and exercise

Twin studies are an elegant method of resolving complex problems, comparing like with like with one variable different.

Exercise is thought to reduce high-risk body fat, but intervention studies are frequently limited by short follow-ups and observational studies by genetic selection. In this elegant study for Finland Leskinen and colleagues studied the effects of a physically inactive or an active lifestyle on high-risk (visceral, liver and intramuscular) fat in twin pairs differerence in leisure-time physical activity habits for over 30 years.

Sixteen middle-aged (50–74 years) same-sex twin pairs (seven monozygotic (MZ), nine dizygotic (DZ)) with long-term difference in physical activity habits during the 32-year-long follow-up.were identified from the Finnish Twin Cohort (TWINACTIVE study).


In within-pair analyses carried out after the adult life-long discordance in physical activity habits, the physically inactive co-twins had 50% greater visceral fat area compared with the active co-twins (mean difference 55.5 cm2. The liver fat score was 170% higher and the intramuscular fat area 54% higher among the inactive co-twins. All the trends were similar for MZ and DZ pairs. Peak oxygen uptake was inversely associated with visceral and intramuscular fat area, with similar trends in intrapair difference correlations. The intrapair difference correlation between visceral and intramuscular fat was also high.
The authors concluded that regular physical activity seems to be an important factor in preventing the accumulation of high-risk fat over time, even after controlling for genetic liability and childhood environment. Therefore, the prevention and treatment of obesity should emphasize the role of regular leisure-time physical activity.

Leskinen et al (2009) Leisure-time physical activity and high-risk fat: a longitudinal population-based twin study International Journal of Obesity 33, 1211–1218;

What nutrients are there in cranberries ?

This review by Pappas and Schaich discusses Vaccinium macrocarpon, the American cranberry, recording a comprehensive list of phytochemical components, and their prevalence in cranberry fruit and its products. Increased dietary consumption of fruits and vegetables may improve increased cardiovascular health and may reduced the risk of cancer, stroke, degenerative diseases, loss of functionality associated with aging, and more . While fruits and vegetables are rich sources of vitamins and minerals, recent attention has focused on the effects of other chemicals present in fruit and vegetables , phytochemical components such as flavonoids, stilbenes, nonnutritive carotenoids, phytoestrogens, terpenes and other diverse phenolics
The possible mechanisms of phytochemical action remain largely unexplained and are the subject of speculation and research. Antioxidant mechanisms have been proposed, especially for cardiovascular health, cancer and age-related degenerative diseases . Phytochemical interact with vital proteins, signal transduction pathways, and bind to pathogen .There is increasing signs that non-nutrient phytochemicals have a place in the health promotion afforded by fruits and vegetables.
Cranberries contain an abundance of flavonoids, especially colored anthocyanins, abundant flavonols, and unique proanthocyanidins, other notable active components include phenolic acids, benzoates, hydroxycinnamic acids, terpenes and organic acids. The health effects of cranberries, cranberry products, and isolated cranberry components in humans and animals, as well as in vitro, are discussed.
Finally, the effects of processing and storage on cranberry phytochemicals is discussed, with afocus on identifying research gaps and novel means to preserve their natural, health-promoting components.
Keywords

( 2009 ) Phytochemicals of Cranberries and Cranberry Products: Characterization, Potential Health Effects, and Processing Stability. Critical Reviews in Food Science and Nutrition vol 49,741-781

Body mass index and coronary heart disease

C G Owen et al ( 2009 ) Is body mass index before middle age related to coronary heart disease risk in later life? Evidence from observational International Journal of Obesity (2009) 33, 866–877;

Although obesity beginning early in life is becoming more common, This study examined the relationship of body mass index (BMI) before 30 years of age to CHD risk in later life.
A systematic review of published studies relating BMI between age 2 and 30 years to later CHD risk using papers reported over 40 + years..

A total of 15 studies provided 17 estimates (731 337 participants, 23 894 CHD events) of the association of early BMI to later CHD outcome. BMI in early childhood (2–6 years, 3 estimates) showed a weak inverse association with CHD risk (RR 0.94, 95% CI 0.82–1.07). BMI in later childhood (7 to <18 years, 7 estimates) and BMI in early adult life (18–30 years, 7 estimates) were both positively related to later CHD risk (RR 1.09, 95% CI 1.00–1.20; RR 1.19, 95% CI 1.11–1.29 respectively). However, there was considerable statistical heterogeneity between study estimates. Results were unaffected by adjustment for social class and/or cigarette smoking, blood pressure and/or total cholesterol, in studies with available data. Gender and year of birth (1900–1976) had little effect on the association.

BMI is positively related to CHD risk from childhood onwards; the associations in young adults are consistent with those observed in middle age. Long-term control of BMI from childhood may be important to reduce the risk of CHD.
Keywords:

infant taste development

Taste is a major determinant of children's food preferences, but much has yet to be known of its development with age. This includes the acceptance of tastes and their developmental changes over the first year, and to compare acceptance across tastes. It is important to know within-subject variability of acceptance across tastes.
In this very interesting study the acceptance of sweet, salty, bitter, sour and umami tastes was measured in three groups of forty-five 3-, 6- and 12-month-old infants looking at ingestion and liking scored by the experimenter.
For each taste, four bottles were used (water, tastant, tastant, water). Acceptance of each taste relative to water was defined using proportional variables based on ingestion or liking. Acceptance over the first year only evolved for sweet taste (marginal decrease) and salty taste (clear increase). At each age, sweet and salty tastes were the most preferred tastes. Reactions to umami were neutral. Sour and bitter tastes were the least accepted ones
During the first year, inter-individual variability increased for all tastes except salty taste.
Schwartz et al 2009 Developmental changes in the acceptance of the five basic tastes in the first year of life British J of Nutrition vol 102 pp 1375-1385

Physical activity in pregancy.

K Melzer et al (2009 ) Pregnancy-related changes in activity energy expenditure and resting metabolic rate in Switzerland . European Journal of Clinical Nutrition, 63, 1185–1191.

This study looked at resting metabolic rate , activity energy expenditure, total energy expenditure and physical activity pattern, that is, duration and intensity (in metabolic equivalents, METs) of activities performed in late pregnancy compared with postpartum in healthy, well-nourished women living in Switzerland.

The subjects were 27 healthy women aged 23–40 years at 38.2 1.5 weeks of gestation and 40.0 7.2 weeks postpartum.
The RMR during late pregnancy was 7480 kJ per day, that is, 1320 760 kJ per day (21.4%) higher than the postpartum resting metabolic rate (P<0.001). Absolute changes in resting metabolic rate were positively correlated with the corresponding changes in body weight (r=0.61, P<0.001). Resting metabolic rate per kg body weight was similar in late pregnancy vs postpartum (P=0.28). Activity energy expenditure per kg during pregnancy and postpartum was 40 13 and 50 20 kJ/kg, respectively (P=0.001). There were significant differences in daily time spent at physical activity pattern, that is, duration and intensity (in metabolic equivalents), <1.5 (1067 vs 998 min, P=0.045), at 2.5 physical activity pattern, that is, duration and intensity (in metabolic equivalents), <3.0 (58 vs 82 min, P=0.002) and physical activity pattern, that is, duration and intensity (in metabolic equivalents), 6 (1 vs 6 min, P=0.014) during pregnancy and postpartum, respectively.

Energy expenditure in healthy women living in Switzerland increases in pregnancy compared with the postpartum state. Additional energy expenditure is primarily attributed to an increase in resting metabolic rate , which is partly compensated by a decrease in Activity energy expenditure. The decrease in physical activity-related energy costs is achieved by selecting less demanding activities and should be taken into account when defining extra energy requirements for late pregnancy in Switzerland.

walking and body mass index

R Santos et al (2009) .Walking and body mass index in a Portuguese sample of adults: a multilevel analysis. European Journal of Clinical Nutrition 63, 1260–1262;


Physical inactivity is an important risk factor for many chronic diseases. This study examined if there were any realtionship between how much individuals walked and body mass index (BMI). This study looked at 9991 adults (5723 women), aged 37.8 9.5 years, from the 2004 Azorean Physical Activity and Health Study. Walking was assessed with the International Physical Activity Questionnaire, and expressed as minutes per week. BMI was calculated from self-reported weight and height.
The results show that, in both genders, and after adjustments for potential confounders, walking was not a significant predictor of BMI.

Predictors of molecular action

In a very interesting paper in Nature , Keiser et al discuss methods of predicting molecular targets for new drugs. It is a comprehensive review of drug – target interactions. Drugs are intended to be selective but often bind to several physiological targets which cold explain side effects and efficacy. The authors selected 3665 drugs and compared these against hundreds of targets defining each target by its ligands. A ligand is a molecule or part of a molecule which binds selectively to one or more specific sites in another molecule eg hormone with receptor. Chemical similarities between drugs and ligands predicted thousands of unanticipated associations. These were than tested in experiments and in a smaller series significant new actions were discovered.
What an opportunity there is for nutritionists to make similar studies with nutrients for example the vitamins and trace elements
Keiser et al 2009 Predicting new molecular targets for known drugs. Nature vol 462 pp 175-181
Hopkins 2009 Predicting promiscuity Nature vol 462 pp 167-8

Key events, dose response in Nutrition

The September edition of Critical Reviews in Food Science and Nutrition ed Fergus Clydesdale( vol 49 issue 8 ) is devoted to Key events Dose Response Framework.
This is a systematic review of key events which occur between the initial dose of a biologically active substance and the effect.
The substance will be
1. ingested, absorbed ( which is liable to be modified by events in the intestine and stomach.)
2. transported or processed by metabolism
3. a interaction or process in the target tissue
4. ultimate effect of interest.
The evaluation of the benefits and risks of a chemical depend upon a knowledge of the dose response in the recipient. A threshold dosage for the biological effect may be defined.
However each human is individual and the biology and genetic make up will differ so it is important to be careful in being too specific about a response. The number of individuals studied, he sensitivity of the methods used to test the chemical’s effect and the frequency and length of the study measurements are important.
The concept of Mode of Action (MOA) is discussed. . A mode of action is a biologically plausible sequence of key events, starting with the interaction of an agent with a cell leading to a observable biological effect. A key event is an observable precursor step that is a necessary part of the mode of action.
The authors believe it is important to define these key events for any biological process.
Finally the review applies these principles to nutrition specifically vitamin A.
Julien et al 2009 The key events dose-response framework: a cross-disciplinary mode- of action base approach to examining dose-response and thresholds. Critical Reviews in Food Science and Nutrition ed Fergus Clydesdale vol 49 pp 682-689
Boobis et al 2009 Application of key events analysis to chemical carcinogens and non-carcinogns. Critical Reviews in Food Science and Nutrition ed Fergus Clydesdale vol 49 pp 690-707
Ross et al 2009 Applcation of a key events dose response analysis to nutrients: a case study with vitamin A ( retinol ) Critical Reviews in Food Science and Nutrition ed Fergus Clydesdale vol 49 pp 708-715

Marathons and risks

The first person to run the Marathon was said to be Pheidippides, a Greek messenger sent from the town of Marathon to Athens to announce that the Persians had been defeated in the Battle of Marathon in August or September, 490 BC. It is said that he ran the entire distance without stopping. In additon to running the first recorded Marathon he was the first to die running a Marathon , he finished his run and and burst into the Athenian assembly, calling "Νενικήκαμεν ( We have won.') before collapsing and dying.

Every year some runners attempting to run the Marathon or a half Marathon die. Over heating or failure to drink sufficient ae the cause. Sometimes previously unknown cardiac anomalies are the cause of death. Often there is no apparent cause.
As reported by Tara Parker-Pope in the New York Times Sport section Thursday October 2nd 2009 a study reported at the American Collee of Cardiology meeting in April gave the risk of death in a marathon at 0.8 per 100, 000 runners. For the triathalon the risk is 1.5 per 100,000 , young non athletes 0.9 per 100,000, young athletes 2.3 per 100,000, childbirth 13 per 100,000, diabetes cause of death 23 per 100,000 . The risk of dying in a car crash is 1 per 6,700

Jane Austen and sweets

Many mothers are cautious about sweets for their children especially towards bed time. This is enthusiasm in youngsters is often attributed to E numbered chemicals.
Jane Austen in her novel Persuasion published in 1818 condemned sweets and sugary confectionary for children as they resulted in excessively high spirits and hyperactivity.
There was also an acceptance that women lived longer than men.

liraglutide and weight management

Few safe and effective drugs are currently available for the treatment of obesity. This interesting paper looks at the use of liraglutide, a drug used in diabetic control on weight reduction. The aim of the study was to assess the effect on bodyweight of liraglutide (at doses up to 3·0 mg per day), in combination with an energy-deficit low-fat diet and physical activity
Liraglutide is a glucagon-like peptide-l (GLP-1) analogue with a 97% structural homology to human GLP-1, a gut-derived incretin hormone. Liraglutide has a long half-life of about 13 h and is given once a day by subcutaneous injection. Liraglutide is used for the treatment of type 2 diabetes mellitus and has benefits for glycaemic control at doses up to 1· 8 mg a day.
Because liraglutide also causes a dose-dependent weight loss, and benefits to the concentration of glycosylated haemoglobin (HbA,,) and systolic blood pressure, and has the potential as an attractive treatment option for both type 2 diabetes and obesity.
The underlying mechanisms for the effects on weight reduction of liraglutide are probably through effects on the gastrointestinal tract and the brain. Native GLP-l suppresses appetite and energy intake in both normal-weight and obese individuals, as well as in people with type 2 diabetes, and delays gastric emptying.
GLP-l receptors are expressed in several brainstem nuclei involved in appetite regulation, and subcutaneously administered liraglutide might also reach these sites.

The study was a double-blind, placebo-controlled 20-week trial, with 564 individuals (18-65 years of age, body-mass index 30-40 kg/ml) who were randomly assigned, to one of four liraglutide doses (1·2 mg, 1·8 mg, 2·4 mg, or 3-0 mg, n=90-95) or to placebo (n=98) administered once a day subcutaneously, or orlistat (120 mg, n=95) three times a day orally. Orlistat blocks intestinal lipase activity. All individuals had a 500 kcal per day energy-deficit diet and increased their physical activity throughout the trial, including the 2-week run-in.
Mean weight loss with liraglutide 1·2-3·0 mg was 4·8 kg, 5·5 kg, 6·3 kg, and 7·2 kg compared with 2·8 kg with placebo and 4·1 kg with orlistat, and was 2·1 kg to 4·4 kg (2·9-6·0) greater than that with placebo.
Liraglutide reduced blood pressure at all doses, and reduced the prevalence of prediabetes (84--96% reduction).
Nausea and vomiting occurred more often in individuals on liraglutide than in those on placebo, but adverse events were mainly transient and rarely led to discontinuation of treatment.
Liraglutide treatment over 20 weeks is well tolerated, induces weight loss, improves certain obesity-related risk factors, and reduces prediabetes.
Astrup, et al (2009 ) Effects of liraglutide in the treatment of obesity:
a randomised, double-blind, placebo-controlled study . The Lancet vol 374 pp1606-16
Comment
Bray 2009 Gastrointestinal hormones and weight management . Lancet vol 374 pp 1570-1