22.3.6. Ketone Bodies Are a Major Fuel in Some Tissues

The major site of production of acetoacetate and 3-hydroxybutyrate is the liver. These substances diffuse from the liver mitochondria into the blood and are transported to peripheral tissues. These ketone bodies were initially regarded as degradation products of little physiological value. However, the results of studies by George Cahill and others revealed that these derivatives of acetyl CoA are important molecules in energy metabolism. Acetoacetate and 3-hydroxybutyrate are normal fuels of respiration and are quantitatively important as sources of energy. Indeed, heart muscle and the renal cortex use acetoacetate in preference to glucose. In contrast, glucose is the major fuel for the brain and red blood cells in well-nourished people on a balanced diet. However, the brain adapts to the utilization of acetoacetate during starvation and diabetes (Sections 30.3.1 and 30.3.2). In prolonged starvation, 75% of the fuel needs of the brain are met by ketone bodies.

"There is an extreme range of normal NEFA availability in
humans. Physiologic hyperinsulinemia can reduce plasma NEFA
concentrations from their normal concentration of <500 to
10–20 mmol/L (2). Under conditions of fasting or adrenergic
stimulation, plasma NEFAs may increase to concentrations
³3000 mmol/L (3). Although there is also a wide range of NEFA
flux, it is not as extreme as the 300-fold variation in plasma
NEFA concentrations. Under hyperinsulinemic conditions,
plasma NEFA flux may decrease to 0.5 mmol · kg21 · min21 (2),
whereas with insulin deficiency (such as during fasting), plasma
NEFA flux may increase to 12.5 mmol · kg21 · min21 (2, 3). During
exercise, plasma NEFA flux may increase to as much as 25
mmol · kg21 · min21."

WHEN GLUCOSE IS HIGH i)Adipose tissue side=> glucose enters adipose tissue->-> leads to NEFA->TG hence no NEFA leaves adipose tissue to enter blood. ii) on the muscle side=> glucose is used b/c NEFA is sparse. WHEN GLUCOSE IS LOW i) on the adipose tissue side=>Since low glucose TG->NEFA w/c leaves into the blood. ii) on the muscle side=> NEFA is plentiful and glucose is sparse=> muscle uses NEFA. iii) In the liver-> if blood glucose falls too much the the NEFA->ketones rxn couples with protein->glucose. <

The more alpha glycerol phosphate available, the more fat is deposited. The more glucose in the cell, the more alpha glycerol phosphate. The more insulin, the more glucose in the cell hence Insulin->glucose->oxidized down to alpha glycerol phosphate->the more fat deposited and kept in the white adipose tissue

REGULATION OF FATTY ACID METABOLISM
"Fatty acids are the major lipid fuel in humans. More than 95%
of all fatty acids are stored as triacylglycerol fatty acids within adipose tissue, which takes up circulating triacylglycerol fatty
acids from VLDL and chylomicron particles. Adipose tissue
releases fatty acids via lipolysis into the circulation, where the
NEFAs serve as the major circulating lipid fuel. Although they
are mostly bound to albumin, the circulating half-life of NEFAs
is only 3–4 min (1).
There is an extreme range of normal NEFA availability in
humans. Physiologic hyperinsulinemia can reduce plasma NEFA
concentrations from their normal concentration of <500 to
10–20 mmol/L (2). Under conditions of fasting or adrenergic
stimulation, plasma NEFAs may increase to concentrations
³3000 mmol/L (3). Although there is also a wide range of NEFA
flux, it is not as extreme as the 300-fold variation in plasma
NEFA concentrations. Under hyperinsulinemic conditions,
plasma NEFA flux may decrease to 0.5 mmol · kg21 · min21 (2),
whereas with insulin deficiency (such as during fasting), plasma
NEFA flux may increase to 12.5 mmol · kg21 · min21 (2, 3). During
exercise, plasma NEFA flux may increase to as much as 25
mmol · kg21 · min21.
This wide range of plasma NEFA availability is possible
because of the exquisite sensitivity of adipose tissue lipolysis to
both insulin (2) and catecholamines (4). Small changes in plasma
insulin concentrations have dramatic effects on adipose tissue
lipolysis, and therefore NEFA availability. The insulin doseresponse
characteristics of NEFA flux were measured in normal
humans by using the pancreatic clamp technique to examine
plasma free insulin concentrations ranging from 0 to <130 pmol/L
(2). At plasma insulin concentrations near zero, NEFA flux is about
double its baseline value; half-maximal suppression of NEFA flux
occurs at plasma free insulin concentrations of <12 pmol/L (total
plasma insulin concentrations of <25 pmol/L). Thus, overnight
postabsorptive plasma insulin concentrations are a significant
restraint to basal NEFA flux. Maximal suppression of NEFA flux in
normal humans occurs at plasma insulin concentrations < 100
pmol/L, easily within the range observed after the ingestion of a
small, carbohydrate-containing meal (5). Catecholamines are
important stimulators of NEFA release under conditions of stress
and during exercise (6, 7). Growth hormone and cortisol also stimulate
lipolysis, but appear to be much less potent than catecholamines
(8, 9). Elevated plasma ketone body concentrations restrain lipolysis (10).
Basal NEFA availability, as measured with isotope-dilution
techniques, exceeds fatty acid oxidation as measured by indirect
calorimetry by <100% (1). Basal NEFA flux exceeds fatty acid
oxidation to a greater extent in individuals with upper-body obesity
(11) and to a lesser extent in trained athletes (12, 13).
Splanchnic tissues account for <40% of basal NEFA uptake
(14). The NEFAs taken up in the splanchnic bed (primarily the
liver) may be oxidized, released as ketone bodies, and released
as VLDL triacylglycerol (15). These VLDL triacylglycerol fatty
acids are then available for reuptake by adipose tissue.
Appropriate regulation of NEFA availability is important for
optimal human health. Excess NEFAs can induce insulin resistance
with respect to muscle glucose uptake (16) and suppression
of endogenous glucose production (17). Other associations with
increased NEFAs include hypertriglyceridemia (18), reduced
hepatic insulin clearance (19, 20), and impaired b-cell insulin
secretion (21). These abnormalities are also commonly associated
with obesity. Thus, it is not surprising that abnormalities of NEFA
flux may be present in some forms of obesity."-Am J Clin Nutr 1998;67(suppl):531S–4S. Printed in USA. © 1998 American Society for Clinical Nutrition

"...In men under 65 with no known heart disease but with risk factors, i.e. LDL of 130 mg/dL or greater, the studies cited showed no difference in all cause mortality. For those men under 65 who had very high LDL levels, the evidence showed that these men might have a slight benefit from taking a statin, but nothing to write home about.

In women who are under 65 there is virtually no evidence that statins do squat. In fact, the report doesn’t even produce evidence that cholesterol lowering does anything for women. The report states that it bases its rationale for treatment of women on an extrapolation of data from men.

In men and women over 65 the studies cited show no evidence that cholesterol lowering brings about any significant decrease in risk for heart disease.

Men of all ages with diagnosed heart disease were the only group that the studies used in this report show receive an actual benefit from taking statins. And even that is slight.

Women who have heart disease and who take statins have a reduced death rate from heart disease but no decrease in all-cause mortality..."

Living organisms thrive best in the milieu and on the
diet to which they were evolutionarily adapted; this is a
fundamental axiom of biology.

Low-Fat Dietary Pattern and Risk of Cardiovascular Disease
The Women's Health Initiative Randomized Controlled Dietary Modification Trial



JAMA. 2006;295:655-666.

Context Multiple epidemiologic studies and some trials have linked diet with cardiovascular disease (CVD) prevention, but long-term intervention data are needed.

Objective To test the hypothesis that a dietary intervention, intended to be low in fat and high in vegetables, fruits, and grains to reduce cancer, would reduce CVD risk.

Design, Setting, and Participants Randomized controlled trial of 48 835 postmenopausal women aged 50 to 79 years, of diverse backgrounds and ethnicities, who participated in the Women's Health Initiative Dietary Modification Trial. Women were randomly assigned to an intervention (19 541 [40%]) or comparison group (29 294 [60%]) in a free-living setting. Study enrollment occurred between 1993 and 1998 in 40 US clinical centers; mean follow-up in this analysis was 8.1 years.

Intervention Intensive behavior modification in group and individual sessions designed to reduce total fat intake to 20% of calories and increase intakes of vegetables/fruits to 5 servings/d and grains to at least 6 servings/d. The comparison group received diet-related education materials.

Main Outcome Measures Fatal and nonfatal coronary heart disease (CHD), fatal and nonfatal stroke, and CVD (composite of CHD and stroke).

Results By year 6, mean fat intake decreased by 8.2% of energy intake in the intervention vs the comparison group, with small decreases in saturated (2.9%), monounsaturated (3.3%), and polyunsaturated (1.5%) fat; increases occurred in intakes of vegetables/fruits (1.1 servings/d) and grains (0.5 serving/d). Low-density lipoprotein cholesterol levels, diastolic blood pressure, and factor VIIc levels were significantly reduced by 3.55 mg/dL, 0.31 mm Hg, and 4.29%, respectively; levels of high-density lipoprotein cholesterol, triglycerides, glucose, and insulin did not significantly differ in the intervention vs comparison groups. The numbers who developed CHD, stroke, and CVD (annualized incidence rates) were 1000 (0.63%), 434 (0.28%), and 1357 (0.86%) in the intervention and 1549 (0.65%), 642 (0.27%), and 2088 (0.88%) in the comparison group. The diet had no significant effects on incidence of CHD (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.90-1.06), stroke (HR, 1.02; 95% CI, 0.90-1.15), or CVD (HR, 0.98; 95% CI, 0.92-1.05). Excluding participants with baseline CVD (3.4%), the HRs (95% CIs) for CHD and stroke were 0.94 (0.86-1.02) and 1.02 (0.90-1.17), respectively. Trends toward greater reductions in CHD risk were observed in those with lower intakes of saturated fat or trans fat or higher intakes of vegetables/fruits.

Conclusions Over a mean of 8.1 years, a dietary intervention that reduced total fat intake and increased intakes of vegetables, fruits, and grains did not significantly reduce the risk of CHD, stroke, or CVD in postmenopausal women and achieved only modest effects on CVD risk factors, suggesting that more focused diet and lifestyle interventions may be needed to improve risk factors and reduce CVD risk.

The project was undertaken between the years 1957-1960 and involved a sample of around 1000 participants who were to be studied over the following 36 months to

test the hypothesis that “The regulation of the level of serum cholesterol and the development of coronary heart disease are related to

1. The caloric balance- sudy showed=>calories per day showed a slight negative association with serum cholesterol (over all age groups) in men but no association in women.

This finding is somewhat puzzling and it is reasonable to inquire if this is related in some way to the level of physical activity. Men in the same physical activity class tend to have higher serum cholesterol levels at lower caloric intake. This finding is contrary to expectation.

2. Level of animal fat intake-study showed=>Paralleling the findings for total calories there is a slight negative association between daily intake of total fat (and also of animal fat) with serum cholesterol level, in men but not in women. This parallel is not surprising given the high correlation between fat intake and total caloric intake. No association between percent of calories from fat and serum cholesterol level was shown;

3. Level of vegetable fat intake- No association...between ratio of plant fat to animal fat intake and serum cholesterol level

4. Level of protein intake-There was a trivial negative correlation between daily protein intake (in grams) and serum cholesterol level

5. Level of cholesterol intake-There is no indication of a relationship between dietary cholesterol and serum cholesterol level. If the intake on animal fat is held constant there is still no relation of cholesterol intake to serum cholesterol level. If (further) a multiple regression is calculated [using animal fat and dietary cholesterol] there is also little suggestion of an association between this pair of variables and serum cholesterol level. IN SUMMARY-

In undertaking the diet study at Framingham the primary interest was, of course, in the relation of diet to the development of coronary heart disease (CHD). It was felt, however, that any such relationship would be an indirect one, diet influencing serum cholesterol level and serum cholesterol level influencing the risk of CHD. However, no relationship could be discerned within the study cohort between food intake and serum cholesterol level.

In the period between the taking of the diet interviews and the end of the 16-year follow-up, 47 cases of de novo CHD developed in the Diet Study group. The means for all the diet variables measured were practically the same for these cases as for the original cohort at risk. There is, in short, no suggestion of any relation between diet and the subsequent development of CHD in the study group… With one exception there was no discernible association between reported diet intake and serum cholesterol level in the Framingham Diet Study Group. The one exception was a weak negative association between caloric intake and serum cholesterol level in men. [As to] coronary heart disease–was it related prospectively to diet. No relationship was found