PDF-available commentaries on obesity and diets

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Hi All,

The below are three PDF-available commentaries on obesity and diets.

In [1], a phrase that appealed to me was:

“the regulatory pathways leading to diet-induced obesity in humans and mice

are likely to be similar”

So, hopefully, studies in rodents on CR pertain to humans also.

In [2], I like:

“the rise in HDL cholesterol in the subjects following the low-carbohydrate

diet (a change observed only by et al.) may reflect a change in HDL

subfractions that occurs with increased intake of saturated fats, and this

change has not been shown to be beneficial. Thus, caution is urged about

overinterpretation of this observation as a beneficial result of a

low-carbohydrate, high-fat diet.”

Also nice, was the last paragraph:

“The recipe for effective weight loss is a combination of motivation,

physical activity, and caloric restriction; maintenance of weight loss is a

balance between caloric intake and physical activity, with lifelong

adherence. For society as a whole, prevention of weight gain is the first

step in curbing the increasing epidemic of overweight and obesity. Until

further evidence is available regarding the long-term benefits of a

low-carbohydrate approach, physicians should continue to recommend a healthy

lifestyle that includes regular physical activity and a balanced diet.”

In [3], there is a discussion of data and some new data in a short report on

different surgical treatment for obesity. The manner in which different

factors such as ghrelin and leptin are altered in different weight and

calorie reduction protocols was of my interest.

Regarding my latest blood tests today, they were after a 10-hour overnight

fast. Figure it out: last time seven days ago not fasting, my glucose was

3.2 versus 3.5-6.0 mM reference range. Fasting it now was 4.5 mM.

Then there were my lipids. My fasting total cholesterol was previously

3.19, now 3.63 mM.triglycerides were reasonably now 0.34 versus previous

0.65 and reference range 4-5.2 mM. That shows what high complex

carbohydrates do when eaten over much time, that is, not fasting or eating

few meals. HDL fasting was 1.12 versus previous not fasting 0.97. The

total cholesterol/HDL ratio was about the same of 3.28. It had been better

previously due to a higher HDL last year.

For my cell blood counts, leukocytes this week were lower at 1.6 versus

4.8-10.8 per 10 to the ninth power. Lymphocytes were also lower, but was

most remarkable was 0.4 versus last week 1.7 and reference range 2.0-7.5

times 10 to the ninth power. That is as low and much lower than the

neutrophils of mine have ever been.

Other markers seemed the same and pretty unremarkable.

Cheers, Al.; email: apater@...

[1] New Engl J Med, 348:2138-2139

Genetic Medicine and Obesity

Aitman, M.D., Ph.D.

Almost all common diseases, such as coronary heart disease, diabetes, and

obesity, are

genetically complex traits. Although they appear to run in families, they have

no clear

pattern of inheritance and their clinical expression has been attributed to the

interaction

between multiple genes and the environment, but the genes have been very hard to

identify.1 Since identification of the genes involved is a crucial step toward

understanding

the molecular pathogenesis of complex diseases, new methods are needed to

accelerate

this process. A study by Schadt and colleagues of obesity in mice may provide

such an

approach.2

Schadt and his colleagues2 used mice derived from mating two standard strains of

inbred

mice. Inbred mice are useful because at every locus they are homozygous for the

alleles

that characterize their strain. In essence, they represent an endless supply of

" identical

twins " that all carry identical autosomes. Second-generation mice derived from

experimental crosses between the two inbred strains were fed a high-fat diet and

characterized with respect to a large number of metabolic and morphometric

traits,

including body weight, fat-pad mass, plasma lipid levels, the presence or

absence of aortic

fatty streaks, and bone density. Those in the upper quartiles of

subcutaneous-fat-pad mass

(referred to as fat mice) and those in the lower quartiles (lean mice) were

selected for

further analysis.

Two studies were performed in the mice. The first was a gene-expression profile,

in which

they used microarrays, or DNA chips, to determine the extent to which about

24,000

genes were differentially expressed in the liver tissues of the fat mice and the

lean mice, as

indicated by levels of messenger RNA. The data were used to form an expression

signature of low and high adiposity. Such a

signature might be used to identify an animal that is susceptible to obesity or

one that is resistant to obesity. The expression

signature in the obese mice fell into two distinct subgroups, suggesting that

even in these inbred mice, there were at least two

different genetic subtypes of obesity.

Obesity is likely to be related to the differential expression of only some of

the genes; to narrow the field of candidates, Schadt

and colleagues performed a genome scan, in which they assessed the extent to

which DNA markers evenly spaced along the

mouse genome were associated with either the clinical traits or the expression

of a given gene across the group of animals

(Figure 1). The results yielded several surprises. First, about half of the

24,000 genes were associated with at least one locus at

a conventional threshold of statistical significance — in other words, the locus

was genetically credible. This is an extraordinarily

high number of significant linkages for a single experiment, given that most

such attempts to map loci of clinical traits seldom

yield more than two or three significant linkages. Second, approximately 30

percent of these loci coincided with the

chromosomal location of the gene itself. This finding implies that the

expression of a significant proportion of all the genes is

controlled by genetic polymorphisms (DNA-sequence variants) within or very close

to each of these genes.

Figure 1. Hunting for Obesity Genes.

Given the immense challenge of identifying genes that underlie common diseases,

which

typically have a complex pattern of inheritance, Schadt and colleagues2 used a

combination of

methods. Using microarrays, they determined the extent to which specific genes

are " turned

on " in the livers of lean mice and fat mice, all of which had been fed a

high-fat diet. (In the

schematic microarrays shown here, red dots indicate high expression, yellow

intermediate, and

green low.) They also obtained measures of adiposity for each mouse. They then

pinpointed

specific parts of the mouse genome that control the regulation of gene

expression (black

arrows) and regions of the genome that regulate adiposity (blue arrows). Some of

the

implicated genomic regions coincide; that is, they regulate both genes that have

different

expression " behaviors " in lean and fat mice and also adiposity itself. Gene A

resides in such a

region, and is a good candidate regulator of obesity. Genes (for example, gene

that are

regulated by regions that do not regulate adiposity are less likely to be

critical regulators of fat

metabolism.

The authors then combined the results of the genome scan with the clinical

phenotypes to identify candidate genes for obesity in

the mice. This analysis excluded many obvious genes that might previously have

been considered strong candidates and

identified new genes, including those that encode major urinary protein 1, a

protein glycosyltransferase, and a

cation-transporting ATPase. These may be primary drivers of obesity in the obese

mice analyzed by Schadt et al.2

Are the results obtained using mouse liver relevant to obesity in humans? The

answer is uncertain, since liver tissue is unlikely to

be available for a similar study in human families. However, the regulatory

pathways leading to diet-induced obesity in humans

and mice are likely to be similar, so the genes that orchestrate the obesity

gene-expression signature in mice are certain to be

evaluated in genetic studies of obesity in humans. These genes — and their

expression signatures — may help to define

subtypes of obesity in humans and also represent new targets for antiobesity

drugs.

More important than simply identifying obesity genes is the idea that this

approach can be applied to any complex trait, given the

availability of appropriate tissue samples from pedigree members. The results of

Schadt et al. show that the approach stands to

advance our understanding of the molecular basis of a wide range of genetically

complex disorders.

References

1.Glazier AM, Nadeau JH, Aitman TJ. Finding genes that underlie complex

traits. Science

2002;298:2345-2349.[Abstract/Full Text]

2.Schadt EE, Monks SA, Drake TA, et al. The genetics of gene expression

surveyed in maize, mouse and man. Nature

2003;422:297-302.[CrossRef][iSI][Medline]

[2] New Engl J Med 348: pages ?-?. Diet, Obesity, and Cardiovascular Risk

O. Bonow, M.D., and H. Eckel, M.D. (2003).

The growing prevalence of obesity and type 2 diabetes in the United States has

attracted

the attention and concern of the medical profession, the media, policymakers,

and the

American public. Recent statistics from the Centers for Disease Control and

Prevention

indicate that nearly two thirds of American adults are overweight (body-mass

index [the

weight in kilograms divided by the square of the height in meters], greater than

25) and

more than 30 percent are frankly obese (body-mass index, greater than 30), that

nearly 8

percent are diabetic, and that 24 percent have the metabolic syndrome. The

metabolic

syndrome is an ominous combination of visceral obesity, atherogenic dyslipidemia

(low

levels of high-density lipoprotein [HDL] cholesterol and elevated levels of

triglycerides),

hypertension, and glucose intolerance that contributes to insulin resistance and

a heightened

risk of diabetes and cardiovascular disease.

These troubling trends have emerged over the past few decades, during which

there has

been a striking increase in caloric intake and a decrease in physical activity

in the U.S.

population. These trends have also spawned a number of best-selling books based

on

popular diet theories, many of which suggest that altering the macronutrient

composition of

the diet can make it easier to curb caloric intake (or even to induce weight

loss without

reducing caloric intake) and can help reduce the risk of heart disease,

diabetes, and other

diseases. Principal among these dietary approaches are those promoting

high-protein,

low-carbohydrate regimens (e.g., the Atkins diet), which have gained widespread

popularity even though the scientific evidence supporting their safety and

efficacy is limited.

A recent review of low-carbohydrate diets reported that weight loss with these

diets is

related to the duration of the diet and the restriction of calories but not to

the reduction in

carbohydrate intake per se and also pointed out the paucity of long-term data.1

In only five

published investigations were subjects following these diets studied for longer

than 90 days,

and none of the studies were randomized or included a comparison group.

The studies reported by Samaha et al. and et al. in this issue of the

Journal (pages

2074–2081 and 2082–2090, respectively) extend knowledge about low-carbohydrate

diets. Each group of investigators randomly assigned obese subjects to either a

low-carbohydrate diet (with high protein and fat

content) or a more standard, reduced-fat diet (with fat constituting less than

30 percent of the total caloric intake but more than

in some extremely low-fat diets). Each study was designed to follow subjects for

more than 90 days. Samaha et al. followed

severely obese subjects (mean body-mass index, 43) with a high prevalence of

diabetes (39 percent) or of the metabolic

syndrome without diabetes (43 percent), whereas et al. studied subjects

with less severe obesity (mean body-mass

index, 34), none of whom had diabetes. Samaha et al. used fixed-carbohydrate

restriction (30 g or less per day), and et

al. used the Atkins diet.

Despite these differences in study populations and dietary approaches, both

studies demonstrated significantly greater weight

reduction with the low-carbohydrate diet than with the reduced-fat diet during

the first six months (average reduction, 6 to 7 kg

vs. 2 to 3 kg). However, the magnitude of the weight-loss difference (4 kg in

both studies) was relatively small, and adherence

in the two diet groups was low. In addition, in the study by et al.,

there was no longer a significant difference in weight

loss between the subjects in the low-carbohydrate group and those in the

reduced-fat group at 12 months. This finding could

reflect the small number of subjects remaining in the study at that time or the

possibility that adherence to the diet was low even

among those who continued in the study. Any approach to caloric restriction that

is not compatible with daily lifestyle patterns is

difficult to maintain over the long term.

In both studies, the reduction in serum triglyceride levels in subjects randomly

assigned to the low-carbohydrate diet might have

been anticipated as a result of their greater weight loss, although it is true

that reduced carbohydrate intake is generally

associated with reduced triglyceride levels. However, the rise in HDL

cholesterol in the subjects following the

low-carbohydrate diet (a change observed only by et al.) may reflect a

change in HDL subfractions that occurs with

increased intake of saturated fats, and this change has not been shown to be

beneficial. Thus, caution is urged about

overinterpretation of this observation as a beneficial result of a

low-carbohydrate, high-fat diet.

The results of both studies demonstrate that initial weight loss is much easier

to achieve than is long-term maintenance of weight

loss. Even if long-term adherence is possible, there are concerns related to the

long-term use of this diet (see Table), since its

high content of fat (particularly saturated fat) is potentially atherogenic. A

wealth of epidemiologic and nutritional data collected

over the past several decades indicates that the consumption of high levels of

saturated fat has adverse consequences on health.

Low-carbohydrate diets may also lack important vitamins and fiber. Moreover, in

marked contrast to the paucity of long-term

data on low-carbohydrate diets, a number of studies reporting the long-term

effects of reduced-fat diets have been reported.

The Finnish Diabetes Prevention Study Group2 and the Diabetes Prevention Program

Research Group3 demonstrated, in

studies involving obese persons with impaired glucose tolerance, that the

combination of a reduced-fat diet and physical activity

over an average of three years facilitated weight reduction equivalent to that

observed in the two current studies of

low-carbohydrate diets and that this combination also appeared to delay the

onset of diabetes. Data from the National Weight

Control Registry have shown that long-term maintenance of weight reduction can

be achieved with a reduced-fat diet

accompanied by regular physical activity. Moreover, others have shown a

reduction in the rate of death from cardiovascular

causes among persons who consume diets high in fruit and vegetables, whole

grains, and fish. Thus, there is evidence to support

the " heart-healthiness " of a balanced diet consisting of a wide variety of

foods, including fruits and vegetables, whole grains,

legumes, lean meat and poultry, and fish, with the total intake of fat

accounting for less than 30 percent of the total number of

calories and the total intake of saturated fat and trans fat accounting for less

than 10 percent of the total calories.

The recipe for effective weight loss is a combination of motivation, physical

activity, and caloric restriction; maintenance of

weight loss is a balance between caloric intake and physical activity, with

lifelong adherence. For society as a whole, prevention

of weight gain is the first step in curbing the increasing epidemic of

overweight and obesity. Until further evidence is available

regarding the long-term benefits of a low-carbohydrate approach, physicians

should continue to recommend a healthy lifestyle

that includes regular physical activity and a balanced diet.

References

1.Bravata DM, L, Huang J, et al. Efficacy and safety of

low-carbohydrate diets: a systematic review. JAMA

2003;289:1837-1850.[Abstract/Full Text]

2.Tuomilehto J, Lindström J, sson JG, et al. Prevention of type 2

diabetes mellitus by changes in lifestyle among

subjects with impaired glucose tolerance. N Engl J Med

2001;344:1343-1350.[Abstract/Full Text]

3.Diabetes Prevention Program Research Group. Reduction in the incidence of

type 2 diabetes with lifestyle intervention or

metformin. N Engl J Med 2002;346:393-403.[Abstract/Full Text]

[3] New Engl J Med 348:2159-2160

Ursula Hanusch-Enserer, Georg Brabant, Roden

Ghrelin Concentrations in Morbidly Obese Patients after Adjustable Gastric

Banding

To the Editor: It has been suggested that the reduction in plasma ghrelin

concentrations in

five morbidly obese patients after treatment with a proximal Roux-en-Y gastric

bypass

contributed to the weight-reducing effect of the surgery.1 This hypothesis has

been

questioned,2 because decreased plasma ghrelin concentrations are present in

obese people

before any intervention and were documented approximately 1.4 years after

gastric bypass

surgery, when weight loss of approximately 36 percent had occurred.

Bariatric surgery is becoming more common — particularly, laparoscopic

adjustable

gastric banding. This procedure, which was recently approved by the Food and

Drug

Administration, causes less dramatic weight loss than gastric bypass.3 Although

both

techniques alter the capacity of the stomach and lead to satiety, the mechanism

responsible

for the greater efficacy of gastric bypass surgery is unclear.

We tested the hypothesis that laparoscopic adjustable gastric banding also

decreases the

plasma ghrelin concentration and that this effect precedes changes in body

weight. To this

end, plasma ghrelin was measured in 12 morbidly obese patients (9 women and 3

men;

mean [±SD] age, 41.8±11.0 years; mean body-mass index [the weight in kilograms

divided by the square of the height in meters], 44.1±3.5) 6 and 12 months after

laparoscopic adjustable gastric banding. The mean weight loss was 18.8 kg (15

percent of

initial body weight) after 6 months and 31.3 kg (25 percent of initial body

weight) after 12 months. The weight loss after six

months was similar to that achieved with dieting and less than that achieved

with gastric bypass.1 The mean fasting plasma

ghrelin concentrations before and after surgery did not differ significantly

(235±64 pmol per liter before surgery, 236±65 pmol

per liter at 6 months, and 255±82 pmol per liter at 12 months), although there

was a trend toward a higher plasma ghrelin

concentration at 12 months. In addition, there were decreases in the plasma

leptin concentration (P<0.001), plasma glucose

concentration (P=0.05), and plasma C-peptide concentration (P<0.001) at this

time, whereas insulin sensitivity, as assessed by

an oral glucose-tolerance test, improved (P=0.03).

These results extend the previous findings1 in that the success of gastric

bypass cannot be explained simply by the reduction of

the gastric volume, but also involves other mechanisms resulting in the

maintenance of the reduced weight despite unchanged

gastric ghrelin secretion. We speculate that the reduction in insulin secretion,

which occurs as a result of improved insulin

sensitivity and weight loss, could stimulate ghrelin secretion, as has recently

been demonstrated in animals.4 The interaction of

insulin and ghrelin could be involved in a central control system that

counteracts a negative energy balance after interventions

designed to induce major weight loss.5

References

1.Cummings DE, Weigle DS, Frayo RS, et al. Plasma ghrelin levels after

diet-induced weight loss or gastric bypass

surgery. N Engl J Med 2002;346:1623-1630.[Abstract/Full Text]

2.Rubino F, Gagner M. Weight loss and plasma ghrelin levels. N Engl J Med

2002;347:1379-1379.[Full Text]

3.Sjöström CD, Peltonen M, Sjöström L. Blood pressure and pulse pressure

during long-term weight loss in the obese:

the Swedish Obese Subjects (SOS) Intervention Study. Obes Res

2001;9:188-195.[Abstract/Full Text]

4.Hewson AK, Tung LY, Connell DW, Tookman L, Dickson SL. The rat arcuate

nucleus integrates peripheral signals

provided by leptin, insulin, and ghrelin mimetic. Diabetes

2002;51:3412-3419.[Abstract/Full Text]

5.Schwartz MW, Woods SC, Seeley RJ, Barsh GS, Baskin DG, Leibel RL. Is the

energy homeostasis system inherently

biased toward weight gain? Diabetes 2003;52:232-238.[Abstract/Full Text]