Introduction

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Small, time limited trials in humans and some case-control studies have indicated that people who eat frequently tend to have lower concentrations of total cholesterol and low density lipoprotein cholesterol than people who eat a gorging diet.^1-6 Results have been less conclusive with respect to concentrations of high density lipoprotein cholesterol, apolipoproteins, and serum glucose and secretion of insulin. ^{1 3 7}

Data from free living populations are limited, and it is not clear whether the effects observed in trials pertain only at the extremes of eating frequency or are continuous over the whole distribution of eating frequency. To investigate this we examined the relation between frequency of eating and concentrations of total cholesterol, low density lipoprotein cholesterol, and high density lipoprotein cholesterol in middle aged men and women in a British population based study.

	Methods

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We used data from the Norfolk cohort of the European prospective investigation into cancer.⁸ This is an ongoing prospective cohort of approximately 25 000 people aged 45-75, resident in Norfolk, and recruited from general practice registers between 1993 and 1997. All participants gave informed consent. At the baseline survey participants completed a detailed health and lifestyle questionnaire and participated in a health examination.

MeasurementsTrained nurses carried out a health check by following standardised protocols. We measured non-fasting serum concentrations of total cholesterol and high density lipoprotein cholesterol and calculated the concentration of low density lipoprotein cholesterol.⁹

QuestionnairesWe assessed frequency of eating by using the question "How many times a day do you eat, including meals, snacks, biscuits with coffee breaks, etc?" We classified participants into five categories of eating frequency: one or two times a day, three times a day, four times a day, five times a day, and six or more times a day. Participants also completed a 160 item food frequency questionnaire.¹⁰ We classified participants as current smokers or non-current smokers. We assessed physical activity by self reported evaluation of amount of activity involved in work: sedentary occupation, standing occupation, physical work (handling of heavy objects and use of tools), and heavy manual work.

Statistical analysisWe used data on participants aged 45-75 who had no missing information on eating frequency, physical activity, lipid concentrations, nutrient intake, blood pressure, weight, height, or waist or hip circumference, which resulted in 14 666 participants (6890 men and 7776 women) being included in these analyses. We analysed the data, separately for men and women, by using the SAS software (SAS Institute, Cary, NC).

	Results

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Mean age did not differ linearly by eating frequency in men but was negatively related to eating frequency in women. Mean body mass index and waist to hip ratio decreased slightly and mean blood pressure increased with increasing reported eating frequency, but trends were not consistent. The percentage of current smokers and the mean alcohol intake were higher in people reporting eating two or fewer times a day. No clear trend for physical activity with eating frequency was observed in women, but men eating more frequently tended to be more likely to participate in physical or heavy manual work.

Mean concentrations of total cholesterol and low density lipoprotein cholesterol decreased with increasing eating frequency in both men and women in a continuous relation. Mean concentration was 0.29 mmol/l lower for total cholesterol and 0.26 mmol/l lower for low density lipoprotein cholesterol in men reporting eating once or twice a day compared with men eating six times or more a day; the differences for mean concentrations of total cholesterol and low density lipoprotein cholesterol in women were 0.22 mmol/l and 0.17 mmol/l. The concentration of high density lipoprotein cholesterol also decreased with increasing eating frequency in both men and women; the overall ratio of low density lipoprotein cholesterol to high density lipoprotein cholesterol decreased with increasing eating frequency.

Increased eating frequency was associated with higher daily intake of energy, as well as of fat, fatty acids, carbohydrate, and protein (see full version on BMJ 's website).

The table shows mean lipid concentrations and blood pressure in men and women after adjustment for age, body mass index, waist to hip ratio, smoking status, physical activity, total energy intake, and alcohol consumption. After adjustment for covariates the significant inverse relation of concentrations of total cholesterol and low density lipoprotein cholesterol to eating frequency was still present, but high density lipoprotein cholesterol concentration was no longer significantly inversely related to eating frequency in men.

Body mass index was weakly significantly associated with increasing eating frequency in men and women (after adjustment for all variables except body mass index) but in opposite directions: negatively in men and positively in women. Waist to hip ratio was still significantly negatively associated with eating frequency only in women (after adjustment for all variables except waist to hip ratio). Blood pressure was not significantly related to eating frequency in women but was positively associated in men.

	Discussion

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The fact that such an effect could be shown in this study is surprising, given the large potential errors in measurement. These include the single measurement of lipid concentrations to characterise individual participants as well as the assessment of eating frequency. Different participants might well interpret the question differently or report their usual eating frequency inaccurately; each person's eating pattern will also vary. Such random measurement errors are likely to obscure or minimise the effect size of any association.

Potential confounding factors
The inverse relation between blood lipid concentrations and eating frequency might be explained by confounding factorsthat is, frequency of eating might simply be a marker of particular lifestyle factors, such as physical activity or alcohol intake, that may directly influence lipid concentrations. However, the relation persisted after adjustment for possible confounding variables including age, obesity, smoking, alcohol consumption, dietary intake, and physical activity. In contrast, blood pressure was not consistently inversely related to eating frequency. We cannot exclude residual confounding, but the specificity of the independent association of eating frequency with lipid concentrations but not with blood pressure makes it unlikely that higher eating frequency was simply a marker for a healthy lifestyle. The association was also consistent in men and women and in different age groups.

Possible mechanisms
Several authors have proposed biological mechanisms that might underlie the lipid lowering effect of increased eating frequency. Gorging animals may have an adaptive metabolismthey are able to store energy from a few periodic loads of food, in contrast to nibbling animals, which feed continuously and have a steady metabolism.¹² This biological process, called "adaptive hyperlipogenesis," is characterised by higher gastrointestinal absorption of glucose and increased activity of pancreatic enzymes; increased ability to produce fat from glucose (that is, an enhanced hepatic lipogenesis possibly mediated by insulin action); increased hepatic synthesis of cholesterol; increased total mass of fat; and higher postprandial peaks of insulin and increased sensitivity to insulin in fat tissue.

Implications of the findings
These metabolic adaptations to gorging may also apply in humans, leading to an increased risk of cardiovascular disease due to changes in lipid profiles and glucose metabolism. Fábry reported 30%, 24%, and 20% prevalence of ischaemic heart disease in men aged 60-64 years reporting eating 3, 3-4, or 5 meals or snacks daily.¹³

Conclusion
Concentrations of total cholesterol and low density lipoprotein cholesterol are negatively and consistently associated with frequency of eating in a general population. We need to consider not just what we eat but how often we eat.

	Acknowledgments

We thank the participants and general practitioners who took part in the study and the staff of EPIC-Norfolk.

	Footnotes

Funding: EPIC-Norfolk is supported by research programme grant funding from the Cancer Research Campaign and Medical Research Council with additional support from the Stroke Association, British Heart Foundation, Department of Health, Europe Against Cancer Programme Commission of the European Union, Ministry of Agriculture, Fisheries and Food, and Wellcome Trust.

Competing interests: None declared.

The full version of this article appears on bmj.com

	References

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(Accepted 2 September 2001)