U.S. patent application number 12/158857 was filed with the patent office on 2011-06-09 for infant nutritional compositions for preventing obesity.
This patent application is currently assigned to N.V. Nutricia. Invention is credited to Gunther Boehm, Johannes Wilhelmus Christina Sijben, Renate Maria Louise Zwijsen.
Application Number | 20110136732 12/158857 |
Document ID | / |
Family ID | 37964343 |
Filed Date | 2011-06-09 |
United States Patent
Application |
20110136732 |
Kind Code |
A1 |
Boehm; Gunther ; et
al. |
June 9, 2011 |
INFANT NUTRITIONAL COMPOSITIONS FOR PREVENTING OBESITY
Abstract
The present invention relates to a method for preventing obesity
later in life by administering a certain nutritional composition to
an infant with the age between 0 and 36 months. The composition
comprises linoleic acid and alpha-linolenic acid.
Inventors: |
Boehm; Gunther; (Echzell,
DE) ; Sijben; Johannes Wilhelmus Christina;
(Wageningen, NL) ; Zwijsen; Renate Maria Louise;
(Utrecht, NL) |
Assignee: |
N.V. Nutricia
Zoetermeer
NL
|
Family ID: |
37964343 |
Appl. No.: |
12/158857 |
Filed: |
December 22, 2006 |
PCT Filed: |
December 22, 2006 |
PCT NO: |
PCT/NL2006/050328 |
371 Date: |
October 28, 2008 |
Current U.S.
Class: |
514/4.8 |
Current CPC
Class: |
A61K 38/1709 20130101;
A61K 31/14 20130101; A61K 31/702 20130101; A61P 3/02 20180101; A61K
31/20 20130101; A61K 31/185 20130101; A23L 33/12 20160801; A61P
3/06 20180101; A61P 25/00 20180101; A61P 9/00 20180101; A61K 31/201
20130101; A61K 31/198 20130101; A61K 31/7016 20130101; A61K 31/575
20130101; A23V 2002/00 20130101; A23L 33/40 20160801; A61K 31/202
20130101; A61P 3/10 20180101; A61P 9/10 20180101; A23L 33/125
20160801; A61K 35/20 20130101; A61K 31/688 20130101; A61P 3/04
20180101; A23V 2002/00 20130101; A23V 2250/1882 20130101; A23V
2250/1878 20130101; A23V 2250/54246 20130101; A23V 2250/612
20130101; A23V 2250/28 20130101; A23V 2250/1846 20130101 |
Class at
Publication: |
514/4.8 |
International
Class: |
A61K 38/00 20060101
A61K038/00; A61P 3/04 20060101 A61P003/04 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 23, 2005 |
EP |
05077972.7 |
Nov 2, 2006 |
NL |
2006/050274 |
Claims
1. (canceled)
2. The method of claim 15, wherein the composition comprises 3-50
wt. % MCFA based on total fatty acids.
3. The method of claim 15, wherein the weight ratio of LN to ALA is
between 2 and 5.
4. The method of claim 15, wherein the composition further
comprises at least 0.5 wt. % of at least one soluble,
non-digestible oligosaccharide based on dry weight of the
composition.
5. The method of claim 9, wherein the at least one soluble,
non-digestible oligosaccharide is selected from the group
consisting of fructo-oligosaccharides, galacto-oligosaccharides,
gluco-oligosaccharides, arabino-oligosaccharides,
mannan-oligosaccharides, xylo-oligosaccharides,
fuco-oligosaccharides, arabinogalacto-oligosaccharides,
glucomanno-oligosaccharides, galactomanno-oligosaccharides, sialic
acid-comprising oligosaccharides and uronic acid
oligosaccharides.
6. The method of claim 15, wherein the composition comprises
galacto-oligosaccharides.
7. The method of claim 6, wherein the composition further comprises
fructo-oligosaccharides.
8. The method of claim 15, wherein said feeding prevents the
development of obesity later-in-life and/or prevents the
development of obesity when said infant has reached an age above 36
months.
9. The method of claim 15, wherein the composition further
comprises: (a) 0.5 to 20 wt. % phospholipids based on weight of
total lipid in the composition; (b) 0.5 to 20 wt. % sphingolipids
based on weight of total lipid in the composition; (c) 0.005 to 10
wt. % cholesterol based on weight of total in the composition;
and/or (d) 0.035 to 1 wt. % choline based on dry weight of the
composition; and (e) 0.001 to 0.1 wt. % uridine based on dry weight
of the composition.
10. The method of claim 15, wherein (a) the lipid component
provides 35 to 55% of the total calories of said composition, (b)
the protein component provides 5 to 15% of the total calories of
said composition, and (c) the digestible carbohydrate component
provides 30 to 60% of the total calories of said composition.
11. The method of claim 15, wherein the composition provides 60-90
kcal/100 ml.
12. The method of claim 15, wherein said feeding prevents the
development of obesity at an age above 12 years.
13. The method of claim 15, wherein said feeding is of an infant
aged below 12 months.
14. The method of claim 15, wherein the composition comprises at
least 0.3 wt. % calcium based on dry weight of the composition.
15. A method to prevent obesity in an a non-obese human infant,
comprising feeding a human infant younger than 36 month of age with
a nutritional composition that comprises a lipid component, a
protein component and a digestible carbohydrate component, wherein
the lipid component comprises: linoleic acid (LA) and a-linolenic
acid (ALA) in a weight ratio of LA to ALA of between 2 and 7; (ii)
less than 15 wt. % LA based on weight of total fatty acids in the
composition; and (iii) at least 1 wt. % ALA based on weight of
total fatty acids in the composition, which composition further
comprises at least one of: (a) 3-50 wt. % MCFA based on total fatty
acids (b) n-6 long chain polyunsaturated fatty acids (LC-PUFA) and
n-3 LC-PUFA in a weight ratio of below 1.5, wherein the content of
the n-6 LC-PUFA and n-3 LC-PUFA are: (1) from 0.02 to 0.8 wt. % n-6
LC-PUFA based on total fatty acids, and (2) at least 0.2 wt. % n-3
LC-PUFA based on total fatty acids.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to preventing obesity later in
life by administering a particular nutritional composition to
non-obese infants with the age below 3 years.
BACKGROUND OF THE INVENTION
[0002] Breast-feeding is the preferred method of feeding infants.
However, there are circumstances that make breast-feeding
impossible or less desirable. In those cases infant formulae are a
good alternative. The composition of modern infant formulae is
adapted in such a way that it meets many of the special nutritional
requirements of the fast growing and developing infant.
[0003] Still it seems that improvements can be made towards the
constitution of infant milk formulae. For example little is known
about the effects of ingredients in the infant formulae on obesity
later in life. The present invention relates to such future
health.
[0004] WO 2005063050 describes a method of increasing lean body
mass and reducing fat body mass in infants by administering to an
infant, term or preterm, a nutritional formula comprising a source
of DHA and ARA. WO 2006057551 relates to an infant nutrition
comprising at least one protease inhibitor, a process for preparing
such an infant nutrition and use of the infant nutrition for the
treatment and/or prevention of childhood obesity and secondary
disorders resulting from childhood obesity. WO 03005836 describes
dietary products for infant, child and adult nutrition which
possess adequate levels and ratios of medium chain fatty acids and
omega-polyunsaturated fatty acids. Consumption of these dietary
products can contribute to the prevention of obesity in developing
individuals and can contribute to a reduction in body fat mass in
individuals who are trying to loose weight or reduce body fat mass
(e.g., obese individuals). WO 2006069918 describes a method of
continuously reducing the circulating level of insulin like growth
factor 1 (IGF-1) in the first few months of the life of an infant
by administering to the infant a nutritional composition comprising
proteins in an amount such that the composition contains less than
2.25 g of protein per 100 kcal. As IGF-1 is known to be a key
control point in nutritional regulation of growth, this may offer a
method of reducing the risk of developing obesity later life.
Aillaud et al, 2006, Progress in Lipid research 45:203-206,
discusses the role of n-6 polyunsaturated fatty acids in the
excessive adipose tissue development and relationship to
obesity.
SUMMARY OF THE INVENTION
[0005] During infancy, body fat, especially subcutaneous fat, has
the important function to maintain an adequate body temperature and
to store energy. Therefore, it is not desirable to generally reduce
body fat mass in infants, because this may interfere with good
growth and development. Hence, a main aim of the present invention
is to design a nutrition to be administered to an infant which
ensures maintenance of normal body composition, growth and
development during infancy but which reduces the accumulation of
excess body fat mass later in life (i.e. after infancy), preferably
during adolescence and/or adulthood.
[0006] The inventors experimentally evidenced that early-in-life
administering nutrition wherein the lipid component is relatively
low in linoleic acid (LA) and wherein the linoleic
acid/alpha-linolenic acid (LA/ALA) ratio is low, results in a
decreased fat mass accumulation, particularly a decreased visceral
fat mass accumulation, later in life. In these experiments, mice
received specific nutrition (low in LA and low LA/ALA)
early-in-life, while a control group did not receive the specific
nutrition. At the later-in-life stage the animal groups received
the same diet high in saturated fat. Surprisingly, no effect on
growth and total body fat mass was observed during the infancy
stage, but, compared to the control group, a decreased total body
fat mass, and specifically a decreased visceral fat mass, was
observed in mice at the adolescence and adulthood stage of life
which had been fed this experimental nutrition during infancy. The
outcome of the experiments is indicative for the effect of the
present infant nutrition composition in the development of obesity
later in life, particularly at an age above 36 months, i.e. during
childhood (age 3-12 years), adolescence (age 13-18 years) and
adulthood (age above 18 years).
[0007] The present invention thus relates to a method for
preventing the development of obesity of a human infant with an age
above 36 months, in other words for preventing development of
obesity later-in-life, said method comprising the administration to
an infant below 36 months of age a nutritional composition
comprising a lipid, protein and digestible carbohydrate component
wherein the lipid component comprises linoleic acid (LA) and
alpha-linolenic acid (ALA) in a weight ratio of LA/ALA between 2
and 7; less than 15 wt. % LA based on total fatty acids; and at
least 1 wt. % ALA based on total fatty acids.
[0008] For certain jurisdictions the invention is also described as
the use of a composition comprising a lipid, protein and digestible
carbohydrate component wherein the lipid component comprises (i)
linoleic acid (LA) and alpha-linolenic acid (ALA) in a weight ratio
of LA/ALA between 2 and 7; (ii) less than 15 wt. % LA based on
total fatty acids; and (iii) at least 1 wt. % ALA based on total
fatty acids, for the manufacture of a nutritional composition to be
administered to a (non-obese) infant with the age below 36 months
for the prevention of obesity. The inventions is preferably
described as a composition to be administered to a non-obese human
with the age below 36 months, said composition comprising a lipid,
protein and digestible carbohydrate component s, wherein the lipid
component comprises linoleic acid (LA) and alpha-linolenic acid
(ALA) in a weight ratio of LA/ALA between 2 and 7; less than 15 wt.
% LA based on total fatty acids; and over 1 wt. % ALA based on
total fatty acids for preventing the development of a disorder,
particularly obesity, when said human has an age above 36
months.
[0009] However, administration of the present low LA formula may
result in deficiencies. In order to reduce or remove the possible
deficiency in fat due to the reduced administration of LA, the
present inventors found that it is advantageous to include medium
chain fatty acids (MCFA) in the present composition which is low in
LA that is administered to an infant below 36 months. LA is an
essential fatty acid, meaning that it cannot be synthesized within
the body. As the present composition comprises a relatively low LA
content, it is important that the LA included in the present
composition is not converted to energy (by fat oxidation) and
therefore not available for anabolic purposes. To reduce the
oxidation of LA in the present low LA composition MCFA can suitably
be added. MCFA are easily mobilized in the bloodstream to provide
long-lasting energy, rather than being stored as fat and thereby
reduce LA oxidation. Additionally it was surprisingly found that a
composition rich in medium chain fatty acids (MCFA) also decreased
total body fat mass later-in-life, while having no effect on body
composition and growth during infancy. However, MCFA did not
specifically reduce visceral fat mass accumulation, but resulted in
an overall reduced fat mass content later-in-life. Including MCFA
thus prevents LA deficiency and has an advantageous effect on
obesity later in life. MCFA are therefore included in the present
composition to a limited amount.
[0010] In addition the inventors recognized that designing an
infant nutrition which is low in LA and with a low ratio of LA/ALA
in order to prevent obesity later-in-life may impair the
bioavailability and incorporation of LA and the n-6 long chain
polyunsaturated fatty acids (LC-PUFA) which are biosynthesized from
LA, particularly arachidonic acid (AA), in membranes of
neurological tissues such as brain and retina. Such incorporation
is of utmost importance in infants, particularly for development of
the visual system and the brain, and is related to increased
intelligence and cognitive skills later-in-life. Thus in an
alternative way to prevent side effects of the present low LA
composition, it was found that it is advantageous to incorporate
n-6 LC-PUFA, especially AA in the present composition that is
administered to an infant below 36 months. It was also found that a
nutrition rich in n-3 LC-PUFA such as docosahexaenoic acid (DHA)
and eicosapentaenoic acid (EPA) also resulted in a decreased total
body fat mass, without showing difference on total body fat mass
and growth during the infancy stage. Thus, n-3 LC-PUFA are also
advantageously incorporated in compositions for reducing obesity
later-in-life. It is a further aim of the present invention to
provide a low LA composition which gives a low insulin
response.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0011] The present invention provides the use of a composition
comprising a lipid, protein and digestible carbohydrate component
wherein the lipid component comprises: [0012] (i) linoleic acid
(LA) and alpha-linolenic acid (ALA) in a weight ratio of LA/ALA
between 2 and 7; [0013] (ii) less than 15 wt. % LA based on total
fatty acids; and [0014] (iii) at least 1 wt. % ALA based on total
fatty acids, and wherein the composition further comprises at least
one selected from the group consisting of: [0015] (a) 3-50 wt. %
medium chain fatty acids (MCFA) based on total fatty acids and
[0016] (b) n-6 long chain polyunsaturated fatty acids (LC-PUPA) and
n-3 LC-PUPA in a weight ratio below 1.5, from 0.02 to 0.8 wt. % n-6
LC-PUPA based on total fatty acids and at least 0.2 wt. % n-3
LC-PUPA based on total fatty acids, for the manufacture of a
nutritional composition to be administered to a (non-obese) infant
with an age below 36 months for the prevention of obesity.
Obesity
[0017] The present composition is administered to a non-obese human
infant with the age below 36 months, preferably below 18 months,
more preferably below 12 months, even more preferably below 6
months. Preferably the present composition is administered to a
non-overweight human with the age below 36 months, preferably below
18 months, more preferably below 12 months, even more preferably
below 6 months of age. The absence or presence of obesity and/or
overweight in an infant can suitably be determined by a physician.
Typically, a non-obese infant below 36 months of age has gender
specific weight-for-length below the 95.sup.th percentile, more
preferably below the 85.sup.th percentile. Gender specific
weight-for-length percentiles have been published by Center for
Disease Control and Prevention (CDC) in 2000. Likewise the presence
or absence of obesity and/or overweight in a human subject above 36
months of age can be easily determined by a physician and/or with
the gender specific weight-for-length percentiles published by
CDC.
[0018] Health related problems are especially associated with a
special form of obesity, namely central obesity. Preferably the
composition is used to prevent central obesity later-in-life. The
term `central obesity` refers to a condition with increased
visceral fat mass. A waist circumference above 102 cm in adult man
or above 88 cm in adult women indicates central obesity. For
children of 3-19 years old appropriate cutoffs for age- and
sex-dependent waist circumferences can be found in Taylor et al,
2000 Am J Clin Nutr 72:490-495.
Low LA Composition
[0019] Herein LA refers to linoleic acid (18:2 n6); ALA refers to
a-linolenic acid (18:3 n3); LC-PUFA refers to long chain
polyunsaturated fatty acids and/or acyl chains comprising at least
20 carbon atoms in the fatty acyl chain and with 2 or more
unsaturated bonds; DHA refers to docosahexaenoic acid (22:6, n3);
EPA refers to eicosapentaenoic acid (20:5 n3); ARA refers to
arachidonic acid (20:4 n6); DPA refers to docosapentaenoic acid
(22:5 n3), and DHGLA refers to dihomogammalinolenic acid (20:3 n6).
Medium chain fatty acids (MCFA) refer to fatty acids and/or acyl
chains with a chain length of 6, 8 or 10 carbon atoms. MCFA may
also be referred to as medium chain triglycerides (MCT).
[0020] The present inventors have found that specific compositions
that have a low LA/ALA ratio and that are low in LA prevent the
occurrence of obesity, especially central obesity. Particularly the
administration of a nutritional composition comprising (i) a LA/ALA
weight ratio between 2 and 7 and (ii) a low LA content (<15 wt.
% based on total fatty acids), resulted in a decreased obesity
later in life.
[0021] The present composition comprises lipid. LA should be
present in a sufficient amount in order to promote a healthy growth
and development, yet in an amount as low as possible to prevent
occurrence of obesity later in life. The composition therefore
comprises less than 15 wt. % LA based on total fatty acids,
preferably between 5 and 14.5 wt. %, more preferably between 6 and
12 wt. %. Based on total dry weight of the composition the present
composition preferably comprises 1.5 to 5 wt. % LA. When in liquid
form, e.g. as ready-to-drink formula, the LA content is preferably
between 0.2 and 0.55 g LA per 100 ml of the liquid composition. The
LA preferably provides between 4 to 8% of total calories in the
present composition.
[0022] ALA should be present in a sufficient amount to promote a
healthy growth and development of the infant. The present
composition therefore comprises at least 1.0 wt. % based on total
fatty acids. Preferably the composition comprises at least 1.6 wt.
% ALA based on total fatty acids, more preferably at least 2.0 wt.
%. Preferably the composition comprises less than 10 wt. % ALA,
more preferably less than 5.0 wt. % based on total fatty acids.
Based on total dry weight of the composition the present
composition preferably comprises at least 0.10 wt. % ALA,
preferably between 0.10 and 0.8 wt. % ALA. When in liquid form,
e.g. as ready-to-drink formula, the ALA content is preferably at
least 30 mg ALA per 100 ml of the liquid composition, preferably
between 50 and 150 mg ALA per 100 ml.
[0023] The weight ratio LA/ALA should be well balanced in order to
prevent obesity, especially central obesity, while at the same time
ensuring a normal growth and development. The proper ratio was
found by the present inventors. The present composition comprises a
weight ratio of LA/ALA between 2 and 7, more preferably between 3
and 6, even more preferably between 4 and 5.5, even more preferably
between 4 and 5. The lipid component comprises less than 15 wt. %
LA based on total fatty acids and a LA/ALA ratio of 2 to 7.
MCFA & LC-PUFA
[0024] Also n-3 LC PUFA was found to reduce both obesity and
central obesity later-in-life and MCFA were found to reduce only
general obesity later-in-life only. This finding further enables
the development of an optimal composition, which preferably
comprises MCFA, but not in excessive amounts, i.e. between 3 and 50
wt. % based on total weight of fatty acids and/or LC-PUFA including
n-6 LC PUFA but with a low n-6 LC-PUFA/n-3 LC-PUFA ratio.
[0025] Medium chain fatty acids (MCFA) are fatty acids and/or acyl
chains with a chain length of 6, 8 or 10 carbon atoms. The present
inventors also found that MCFA contribute to a reduced fat mass
later in life. LA is an essential fatty acid, meaning that it
cannot be synthesized within the body. As the present composition
comprises a relatively low LA content, it is important that the LA
included in the present composition is not converted to energy (by
fat oxidation) and therefore not available for anabolic purposes.
To reduce the oxidation of LA in the present low LA composition
MCFA can suitably be added. MCFA are easily mobilized in the
bloodstream to provide energy, rather than being stored as fat and
thereby reduce LA oxidation. Therefore, the present composition
preferably comprises at least 3 wt. % MCFA based on total fatty
acids, more preferably at least 10 wt. %, even more preferably 15
wt. %.
[0026] The present inventors found that MCFA reduces body fat
deposition with no preference for central fat mass. Therefore, the
present low LA and low LA/ALA composition advantageously comprises
less than 50 wt. % MCFA based on total fatty acids, more preferably
less than 40 wt. %, even more preferably less than 25 wt. %.
Preferably the present composition comprises LC-PUPA. The present
inventors found that LC-PUPA reduce obesity later in life, more
preferably central obesity. More preferably, the present
composition comprises n-3 LC-PUPA, even more preferably EPA, DPA
and/or DHA, even more preferably DHA. It was found that these n-3
LC-PUPA decrease obesity.
[0027] Since a low concentration of DHA, DPA and/or EPA is already
effective and normal growth and development are important, the
content of n-3 LC-PUPA in the present composition, preferably does
not exceed 15 wt. % of the total fatty acid content, preferably
does not exceed 10 wt. %, even more preferably does not exceed 5
wt. %. Preferably the present composition comprises at least 0.2
wt. %, preferably at least 0.5 wt. %, more preferably at least 0.75
wt. % n-3 LC-PUPA of the total fatty acid content. For the same
reason, the EPA content preferably does not exceed 5 wt. % of the
total fatty acid, more preferably does not exceed 1 wt. %, but is
preferably at least 0.025 wt. %, more preferably at least 0.05 wt.
% of the total fatty acid. The DHA content preferably does not
exceed 5 wt. %, more preferably does not exceed 1 wt. %, but is
preferably at least 0.1 wt. % of the total fatty acid. The DPA
content preferably does not exceed 1 wt. %, more preferably does
not exceed 0.5 wt. % of the total fatty acid content, but is
preferably at least 0.01 wt. % of the total fatty acid. Preferably
as a source of n-3 LC-PUFA single cell oil, preferably algal oil,
fungal oil and/or microbial oil is used, since these oil sources
have a low EPA/DHA ratio, which results in an increased
anti-obesity effect. More preferably the present composition
comprises fish oil (more preferably tuna oil). Fish oil has a
higher EPA concentration which is advantageous since EPA is
precursor of eicosanoids which have an additional anti-obesity
effect.
[0028] As the group of n-6 fatty acids, especially arachidonic acid
(AA) and LA as its precursor, counteracts the group of n-3 fatty
acids, especially DHA and EPA and ALA as their precursor, the
present composition comprises relatively low amounts of AA. The n-6
LC-PUFA content preferably does not exceed 5 wt. %, more preferably
does not exceed 0.8 wt. %, more preferably does not exceed 0.75 wt.
%, even more preferably does not exceed 0.5 wt. % based on total
fatty acids. Since AA is important in infants for optimal
functional membranes, especially membranes of neurological tissues,
the amount of n-6 LC-PUFA is preferably at least 0.02 wt. %, more
preferably at least 0.05 wt. %, even more preferably at least 0.1
wt. % based on total fatty acids, more preferably at least 0.25 wt.
%. The present composition preferably contains less than 1 wt. % AA
based on total fatty acids. The presence of AA is advantageous in a
composition low in LA since it remedies LA deficiency. The presence
of, preferably low amounts, of AA is beneficial in nutrition to be
administered to infants below the age of 6 months, since for these
infants the infant formulae is generally the only source of
nutrition.
[0029] The weight ratio n-6 LC-PUPA/n-3 LC-PUPA in the present
infant nutrition is preferably low in order to prevent obesity
later in life. Preferably the composition comprises a weight ratio
of n-6 LC-PUPA/n-3 LC-PUPA below 1.5, more preferably below 1.0,
even more preferably below 0.6.
[0030] LA, ALA, MCFA and/or LC-PUPA are preferably provided as free
fatty acids, in triglyceride form, in diglyceride form, in
monoglyceride form, in phospholipid form, or as a mixture of one of
more of the above. Preferably the present composition contains
LC-PUFA in triglyceride and/or phospholipid form, even more
preferably phospholipid form since LC-PUFA in phospholipid form are
better incorporated into membranes. Preferably, the present
composition contain MCFA in triglyceride form
[0031] Table 1 gives preferred characteristics of the lipid
component of the present composition
TABLE-US-00001 TABLE 1 preferred more preferred most preferred LA
(wt. % based on total <15 5-14.5 6-12 fatty acids) ALA (wt. %
based on total >1 1.6-10 2.0-5.0 fatty acids) Weight ratio
LA/ALA 2-7 3-6 4-5.5 MCFA (wt. % based on 3-50 10-40 15-25 total
fatty acids) n-6 LC-PUFA (wt. % based 0.02-0.8 0.05-0.75 0.25-0.5
on total fatty acids, sum of AA + DHGLA) n-3 LC-PUFA (wt. % based
>0.2 0.25-15 0.75-5 on total fatty acids, sum of EPA, DPA and
DHA) Ratio n-6 LC-PUFA/ <1.5 <1.0 <0.6 n-3 LC-PUFA
[0032] Preferably the present composition comprises at least one,
preferably at least two lipid sources selected from the group
consisting of linseed oil (flaxseed oil), rape seed oil (including
colza oil, low erucic acid rape seed oil and canola oil), salvia
oil, perilla oil, purslane oil, lingonberry oil, sea buckthorn oil,
hemp oil, high oleic sunflower oil, high oleic safflower oil, olive
oil, marine oils, microbial oils, black currant seed oil, echium
oil, butter fat, coconut oil and palm kernel oil. Preferably the
present composition comprises at least one, preferably at least two
lipid sources selected from the group consisting of linseed oil,
rapeseed oil, coconut oil, high oleic sunflower oil, butter oil and
marine oil.
Phospholipids, cholesterol and sphingolipids
[0033] Since LA is an essential fatty acid and n-6 LC-PUFA are
important membrane components (including in neurological tissue
membranes), the small amount of LA and optionally n-6 LC-PUFA
present in the composition of the invention are preferably
incorporated into neurological cell membranes as efficiently as
possible. This can be achieved by providing lipidic membrane
components, including cholesterol, phospholipids and/or
sphingolipids in the present low LA composition. The presence of
these components increases the incorporation of PUFA, including LA
and n-6 LC-PUFA in membranes, thereby preventing oxidation.
[0034] The term phospholipids as used in the present invention
particularly refers to glycerophospholipids. Glycerophospholipids
are a class of lipids formed from fatty acids esterified to the
hydroxyl groups on carbon-1 and carbon-2 of the backbone glycerol
moiety and a negatively-charged phosphate group attached to
carbon-3 of the glycerol via an ester bond, and optionally a
choline group (in case of phosphatidylcholine), a serine group (in
case of phosphatidylserine), an ethanolamine group (in case of
phosphatidylethanolamine), an inositol group (in case of
phosphatidylinositol) or a glycerol group (in case of
phosphatidylglycerol) attached to the phosphate group. Preferably
the present composition contains phosphatidylcholine (PC),
phosphatidylserine, phosphatidylinositol and/or
phosphatidylethanolamine, more preferably at least
phosphatidylcholine.
[0035] A preferred source for phospholipids, particularly PC, is
soy lecithin, egg lipid, and/or buttermilk fat. Hence the present
composition preferably comprises soy lecithin, egg lipid and/or
buttermilk fat, more preferably soy lecithin and/or buttermilk
fat.
[0036] Preferably the present composition comprises 0.5 to 20 wt. %
phospholipids based on total lipid, more preferably 1 to 10 wt. %,
even more preferably 4 to 8 wt %. As also found by the inventors,
oral administration of a composition comprising phospholipids
and/or sphingolipids and/or cholesterol has the further advantage
that it decreases the post-prandial insulin response (see example
2). High insulin levels stimulate glucose uptake in adipose tissue,
resulting in an increased adipose tissue mass. In infants high
insulin levels also contribute to increased visceral adipocyte
proliferation, at least partly due to the increased glucose uptake.
Therefore the present composition for infants aimed to decrease
obesity later in life preferably comprises phospholipids,
sphingolipids and/or cholesterol, more preferably
phospholipids.
[0037] Preferably the present composition comprises 0.5 to 20 wt. %
sphingolipids based on total lipid, more preferably 1 to 10 wt. %,
even more preferably 4 to 8 wt. %. The term sphingolipids as in the
present invention particularly refers to glycolipids with an amino
alcohol sphingosine. The sphingosine backbone is O-linked to a
(usually) charged headgroup such as ethanolamine, serine or choline
backbone. The backbone is also amide linked to a fatty acyl group.
Sphingolipids include sphingomyelin, ceramides, and
glycosphingolipids. Preferably the present composition contains
sphingomyelin and/or glycosphingolipids. Glycosphingolipids are
ceramides with one or more sugar residues joined in a
.beta.-glycosidic linkage at the 1-hydroxyl position.
Glycosphingolipids may be further subdivided into cerebrosides,
globosides and gangliosides. Cerebrosides have a single glucose or
galactose at the 1-hydroxy position, while gangliosides have at
least three sugars, one of which must be sialic acid.
Sphingomyelins have a phosphorylcholine or phosphoroethanolamine
molecule esterified to the 1-hydroxy group of a ceramide.
Preferably the present composition contains gangliosides.
[0038] Preferably the composition comprises sphingolipids, more
preferably sphingomyelin and/or gangliosides. Preferably the
present composition comprises at least one ganglioside selected
from the group consisting of GM3 and GD3.
[0039] Preferably the present composition comprises 0.5 to 20 wt. %
(sphingolipids plus phospholipids) based on total lipid, more
preferably 1 to 10 wt. %, even more preferably 4 to 8 wt. %.
[0040] Dietary cholesterol modulates lipid metabolism by the
stimulation of chain elongation of the fatty acyl chains
(phospholipids, free fatty acids; diglycerides and triglycerides).
By affecting the conversion of essential fatty acids to their
LC-PUPA successors, the production of essential membrane building
block is increased and thus the synthesis and function of neuronal
membranes in the brain. Consequently, the use of essential lipids
for energy metabolism is reduced. Furthermore, cholesterol is an
essential building block of membranes, and is necessary to increase
membrane synthesis. Cholesterol is therefore advantageously
included in the present low LA composition to prevent side effects
of the low LA in the present formula.
[0041] Moreover, dietary cholesterol during infancy inhibits the
endogenous cholesterol synthesis and programmes the endogenous
cholesterol synthesis to lower levels. Consequently, reduced blood
cholesterol levels later in life will be achieved. This results in
a drop of LDL-cholesterol value in blood and a raise of HDL
cholesterol value in blood during adolescent and adulthood. Hence
the present invention also provides the use of a composition
comprising a lipid, protein, digestible carbohydrate and
cholesterol for the manufacture of a nutritional composition to be
administered to an infant with the age below 36 months for the
prevention of cardiovascular disease, atherosclerosis and/or high
blood cholesterol levels later in life. This nutritional
composition preferably has at least part of the nutrient
requirement described in the present application, e.g.
advantageously includes the non-digestible oligosaccharide, lactose
and/or lipid component as described herein.
[0042] Preferred sources of cholesterol are milk fat, buttermilk
fat, butterserum fat and egg lipids. Hence the present composition
preferably comprises buttermilk fat, butterserum fat and/or egg
lipids. The present composition preferably comprises at least 0.005
wt. % cholesterol based on total fat, more preferably at least 0.01
wt. %, more preferably at least 0.05 wt. %., even more preferably
at least 0.1 wt. %. Preferably the amount of cholesterol does not
exceed 10 wt. % based on total lipid, more preferably does not
exceed 5 wt. %, even more preferably does not exceed 1 wt. % of
total lipid. Most preferably the amount of cholesterol is 0.5 to
0.7 wt. % based on total lipid.
[0043] Preferably the amount of cholesterol does not exceed 1 wt. %
based on total fat, more preferably does not exceed 0.5 wt. %.
Uridine and Choline
[0044] Alternatively, the present low LA composition comprises a
source of uridine and choline. In humans receiving the present low
LA composition, enhanced membrane synthesis is preferably achieved
by providing the two main precursors for phosphatidyl choline or
other major membrane phospholipids in brain, namely a source of
uridine and choline. Uridine is metabolized to cytidine and
subsequently phosphorylated to CTP; choline is metabolized to
phosphocholine. Subsequently, CTP and phosphocholine result in
CDP-choline formation, a key step in phospholipid biosynthesis
pathway. Thus, the combination of a source of uridine and choline
stimulate phospholipid biosynthesis. The increase of phospholipid
synthesis caused by uridine and choline supplementation also
enhances the incorporation of arachidonic acids and other LC-PUPA
into the mayor phospholipids in the brain, which makes it
particularly suitable for counteracting side effects of the present
low LA composition.
[0045] Preferably the composition comprises a source of uridine and
choline. Choline is preferably added as choline chloride. The
present composition preferably comprises choline chloride. The
present composition preferably comprises at least 0.035 wt. %
choline based on dry weight of the composition, more preferably at
least 0.045 wt. %. Preferably the present composition comprises no
more than 1 wt. % choline based on total dry weight or the present
composition, more preferably below 0.5 wt. %, even more preferably
below 0.1 wt. %. The presence of choline has the further advantage
that it oxidizes fat, results in an increase of lean body mass and
enhances the fat clearance of blood into cells. Choline has the
further advantage that it is an excellent methyldonor. In stages of
quick growth such as in infancy, a sufficient amount of methyldonor
is important to sustain differentiation and regulation and thereby
result in a proper metabolic imprinting via DNA methylation. A
proper metabolic imprinting is important for preventing obesity
later in life. Therefore the composition of the present invention
preferably comprises choline.
[0046] In a preferred embodiment the present composition comprises
uridine in the form of a nucleotide, nucleoside and/or base.
Preferably the composition comprises 0.001 to 0.1 wt. % uridine
based on dry weight of the present composition, more preferably
0.002 to 0.05 wt. %, most preferably 0.002 to 0.025 wt. %. More
preferably the composition comprises uridine in nucleotide form.
The uridine is preferably in the nucleotide monophosphate,
diphosphate or triphosphate form, more preferably in nucleotide
monophosphate form. The uridine nucleotides can be monomeric,
dimeric or polymeric (including RNA). The nucleotides preferably
are present as a free acid or in the form of a salt, more
preferably monosodium salt. Preferably, the present composition
comprises uridine 5'-monophospate and/or salts thereof
(collectively abbreviated to UMP), in particular monosodium salts
thereof. Preferably the composition comprises 0.001 to 0.1 wt. %
UMP based on dry weight of the present composition, more preferably
0.002 to 0.05 wt. %, most preferably 0.002 to 0.025 wt. %. UMP is
preferably be added to the composition in a mixture of nucleotides.
Preferably the present composition contains yeast RNA as a source
of UMP. Preferably the composition comprises UMP and choline.
Preferably the composition comprises a source of uridine, choline
and phospholipids. Preferably the composition comprises UMP,
choline and phospholipids. This combination even further stimulates
membrane formation and is therefore particularly suitable for
inclusion in the present low LA composition.
Non-Digestible Oligosaccharides
[0047] As already described above high blood insulin levels
stimulate glucose uptake in adipose tissue, resulting in an
increased adipose tissue mass. In infants the high insulin levels
contribute to increased proliferation of adipocytes, at least
partly due to the increased glucose uptake, and thereby in an
increased chance of obesity later in life.
[0048] The present composition therefore preferably maintains low
insulin levels. It was found that non-digestible oligosaccharides
(NDO) that can be fermented (particularly galacto-oligosaccharides)
have a blood insulin tempering effect, and consequently contribute
to a reduced change on obesity later-in-life.
[0049] Additionally it was also recognized that infants ingest more
calories when bottle fed compared to a situation where breast
feeding occurs. In addition to the compositional features of the
lipid component as suggested in the present invention, the
effectiveness can further be improved by reducing caloric intake.
Limiting dosage of the nutritional composition is however not a
feasible option for infants. The present inventors have found that
for this purpose advantageously the present composition comprises
non-digestible oligosaccharides.
[0050] Fermentation of these non-digestible oligosaccharides,
preferably galacto-oligosaccharides, further results in the
formation of intestinal acetate which is taken up and will enter
the circulation and the liver, thereby serving advantageously as a
lipid elongation precursor and/or advantageously stimulating the
conversion of LA to AA.
[0051] Therefore, the present composition preferably comprises the
present lipid component and a non-digestible oligosaccharide which
can be fermented. The combination of the present lipid component
and the non-digestible oligosaccharides synergistically reduces the
obesity later in life. Preferably the present composition comprises
non-digestible oligosaccharides with a degree of polymerisation
(DP) between 2 and 60. The composition preferably prevents the
onset of insulin resistance. The non-digestible oligosaccharide is
preferably selected from the group consisting of
fructo-oligosaccharides (including inulin),
galacto-oligosaccharides (including transgalacto-oligosaccharides),
gluco-oligosaccharides (including gentio-, nigero- and
cyclodextrin-oligosaccharides), arabino-oligosaccharides,
mannan-oligosaccharides, xylo-oligosaccharides,
fuco-oligosaccharides, arabinogalacto-oligosaccharides,
glucomanno-oligosaccharides, galactomanno-oligosaccharides, sialic
acid comprising oligosaccharides and uronic acid oligosaccharides.
Preferably the present composition comprises
fructo-oligosaccharides, galacto-oligosaccharides and/or
galacturonic acid oligosaccharides, more preferably
galacto-oligosaccharides, most preferably
transgalacto-oligosaccharides. In a preferred embodiment the
composition comprises a mixture of transgalacto-oligosaccharides
and fructo-oligosaccharides. Preferably the present composition
comprises galacto-oligosaccharides with a DP of 2-10 and/or
fructo-oligosaccharides with a DP of 2-60. The
galacto-oligosaccharide is preferably selected from the group
consisting of transgalacto-oligosaccharides, lacto-N-tetraose
(LNT), lacto-N-neotetraose (neo-LNT), fucosyl-lactose, fucosylated
LNT and fucosylated neo-LNT. In a particularly preferred embodiment
the present method comprises the administration of
transgalacto-oligosaccharides ([galactose].sub.n-glucose; wherein n
is an integer between 1 and 60, i.e. 2, 3, 4, 5, 6, . . . , 59, 60;
preferably n is selected from 2, 3, 4, 5, 6, 7, 8, 9, or 10).
Transgalacto-oligosaccharides (TOS) are for example sold under the
trademark Vivinal.TM. (Borculo Domo Ingredients, Netherlands).
Preferably the saccharides of the transgalacto-oligosaccharides are
.beta.-linked. Fructo-oligosaccharide is a NDO comprising a chain
of .beta. linked fructose units with a DP or average DP of 2 to
250, more preferably 10 to 100. Fructo-oligosaccharide includes
inulin, levan and/or a mixed type of polyfructan. An especially
preferred fructo-oligosaccharide is inulin. Fructo-oligosaccharide
suitable for use in the compositions is also already commercially
available, e.g. Raftiline.RTM.HP (Orafti). Uronic acid
oligosaccharides are preferably obtained from pectin degradation.
Hence the present composition preferably comprises a pectin
degradation product with a DP between 2 and 100. Preferably the
pectin degradation product is prepared from apple pectin, beet
pectin and/or citrus pectin. Preferably the composition comprises
transgalacto-oligosaccharide, fructo-oligosaccharide and a pectin
degradation product. The weight ratio
transgalacto-oligosaccharide:fructo-oligosaccharide:pectin
degradation product is preferably 20 to 2:1:1 to 3, more preferably
12 to 7:1:1 to 2.
Lactose
[0052] The maintenance of insulin sensitivity can be further
improved by inclusion of a low glycaemic carbohydrate in the
present composition, preferably lactose. Hence, the present
composition preferably comprises in addition to the present lipid
component, non-digestible oligosaccharides and/or lactose. The
present composition preferably comprises a digestible carbohydrate
component, wherein at least 35 wt. %, more preferably at least 50
wt. %, more preferably at least 75 wt. %, even more preferably at
least 90 wt. %, most preferably at least 95 wt. % is lactose. The
present composition preferably comprises at least 25 grams lactose
per 100 gram dry weight of the present composition, preferably at
least 40 grams lactose/100 gram.
Hydrolyzed Protein
[0053] Preferably the composition comprises hydrolyzed casein
and/or hydrolyzed whey protein. It was found that administration of
a composition wherein the protein comprises hydrolyzed casein and
hydrolyzed whey results in reduced post-prandial levels of both
insulin and glucose compared to the administration of a composition
comprising intact casein and intact whey protein. Increased levels
of both insulin and glucose indicate a form of insulin resistance
in formula fed infants, which is believed contribute to the
development of obesity later-in-life. The present composition
preferably comprises at least 25 wt. % peptides with a chain length
of 2 to 30 amino acids based on dry weight of protein. The amount
of peptides with a chain length between 2 and 30 amino acids can
for example be determined as described by de Freitas et al, 1993,
J. Agric. Food Chem. 41:1432-1438. The present composition
preferably comprises casein hydrolysate and/or whey protein
hydrolysate, more preferably casein hydrolysate and whey protein
hydrolysate because the amino acid composition of bovine casein is
more similar to the amino acid composition found in human milk
protein and whey protein is easier to digest and found in greater
ratios in human milk. The composition preferably comprises at least
50 wt. %, preferably at least 80 wt. %, most preferably about 100
wt. % of a protein hydrolysate, based on total weight of the
protein. The present composition preferably comprises a protein
with a degree of hydrolysis of the protein between 5 and 25%, more
preferably between 7.5 and 21%, most preferably between 10 and 20%.
The degree of hydrolysis is defined as the percentage of peptide
bonds which have been broken down by enzymatic hydrolysis, with
100% being the total potential peptide bonds present.
Casein
[0054] Casein is advantageously present since it increases the
gastric emptying times by forming a curd in the stomach, thereby
increasing satiety. As satiety induction is highly desirable, see
above, the present composition preferably comprises casein. When
the composition is in liquid form, e.g. as a ready-to-drink liquid,
the composition preferably comprises at least 0.5 g casein per 100
ml, preferably between 0.5 and 5 gram casein per 100 ml. Preferably
the composition comprises at least 4 wt. % casein based on dry
weight. Preferably the casein is intact and/or non-hydrolyzed.
Calcium
[0055] Preferably the composition comprises calcium. Increased
dietary calcium decreases the intracellular calcium concentration
in adipocytes and this may in decrease adipocytes late stage
differentiation and lipid filling. Preferably the calcium is added
with as counter anion carbonate, hydroxide, chloride, phosphate,
lactate, gluconate, and/or citrate. Preferably the composition
comprises at least 0.1 wt. % calcium based on dry weight of the
composition, preferably at least 0.25 wt. % most preferably at
least 0.4 wt. %. Preferably the composition comprises less than 5
wt. % calcium based on dry weight of the composition, preferably
less than 2 wt. %, more preferably less than 1 wt. %.
Nutritional Composition
[0056] The present composition is particularly suitable for
providing the daily nutritional requirements to an infant with the
age below 36 months, particularly an infant with the age below 24
months, even more preferably an infant with the age below 18
months, most preferably below 12 months of age. Hence, the present
composition comprises a lipid, protein and digestible carbohydrate
component wherein the lipid component provides preferably 35 to 55%
of the total calories, the protein component preferably provides 5
to 15% of the total calories and the digestible carbohydrate
component preferably provides 30 to 60% of the total calories.
Preferably the present composition comprises a lipid component
providing 40 to 50% of the total calories, a protein component
provides 6 to 12% of the total calories and a digestible
carbohydrate component provides 40 to 50% of the total calories.
When in liquid form, e.g. as a ready-to-feed liquid, the
composition preferably comprises 2.1 to 6.5 g lipid per 100 ml,
more preferably 3.0 to 4.0 g per 100 ml. Based on dry weight the
present composition preferably comprises 12.5 to 40 wt. % lipid,
more preferably 19 to 30 wt. %.
[0057] The amount of saturated fatty acids is preferably below 58
wt. % based on total fatty acids, more preferably below 45 wt. %.
The concentration of monounsaturated fatty acids preferably ranges
from 17 to 60% based on weight of total fatty acids.
[0058] The present composition is not human breast milk. The
present composition preferably comprises (i) vegetable lipid and/or
animal (non-human) fat; and/or (ii) vegetable protein and/or animal
(non-human) milk protein. Examples of animal milk protein are whey
protein from cow's milk and protein from goat milk. The present
composition preferably does not comprise a proteinase inhibitor,
preferably not a trypsin inhibitor, chymotrypsin inhibitor or
elastase inhibitor. The present composition is not human milk.
[0059] The present composition preferably comprises at least 50 wt.
% protein derived from non-human milk based on total protein, more
preferably at least 90 wt. %. Preferably the present composition
comprises at least 50 wt. % cow's milk derived protein based on
total protein, more preferably at least 90 wt. %. Preferably the
present composition comprises acid whey and/or sweet whey with a
reduced concentration of glycomacropeptide. Preferably the present
composition comprises protein derived from .beta.-casein and/or
a-lactalbumin. The present composition preferably comprises casein
and whey proteins in a weight ratio casein:whey of 10:90 to 90:10,
more preferably 20:80 to 80:20. The term protein as used in the
present invention refers to the sum of proteins, peptides and free
amino acids. The present composition preferably contains 1.5 to 3.0
g protein/100 kcal, preferably between and 1.8 and 2.25 g/100 kcal,
even more preferably between and 1.8 and 2.0 g/100 kcal.
[0060] The present composition is preferably administered in liquid
form. In order to meet the caloric requirements of the infant, the
composition preferably comprises 50 to 200 kcal/100 ml liquid, more
preferably 60 to 90 kcal/100 ml liquid, even more preferably 60 to
75 kcal/100 ml liquid. This caloric density ensures an optimal
ratio between water and calorie consumption. The osmolarity of the
present composition is preferably between 150 and 420 mOsmol/l,
more preferably 260 to 320 mOsmol/l. The low osmolarity aims to
reduce the gastrointestinal stress. Stress can induce obesity.
[0061] Preferably the composition is in a liquid form, with a
viscosity below 35 cps as measured in a Brookfield viscometer at
20.degree. C. at a shear rate of 100 s.sup.-1. Suitably, the
composition is in a powdered from, which can be reconstituted with
water to form a liquid, or in a liquid concentrate form, which
should be diluted with water.
[0062] When the composition is a liquid form, the preferred volume
administered on a daily basis is in the range of about 80 to 2500
ml, more preferably about 450 to 1000 ml per day.
Infant
[0063] Adipocytes, including visceral adipocytes, proliferate
during the first 36 months of life as well as (more limited) in
puberty. The amount of adipocytes is an important determinant in
the degree of obesity later-in-life. Hence the present composition
is administered to the infant during the first 3 years of life. It
was found that there is a predominance of proliferation of
(visceral) adipocytes in the first 12 months of life (with an
optimum in perinatal adipocyte proliferation). Hence, it is
particularly preferred that the present composition is administered
to the infant in this period of life. The present composition is
therefore advantageously administered to a human of 0-24 months,
more preferably to a human of 0-18 months, most preferably to a
human of 0-12 months. The present invention particularly aims to
prevent obesity later-in-life and is preferably not an obesity
treatment. Hence, the present composition is preferably
administered to an infant not suffering from obesity or childhood
obesity, particularly a non-obese infant more preferably an infant
that does not suffer from overweight. The present composition is
preferably administered orally to the infant.
Application
[0064] The present invention also aims to prevent the occurrence of
obesity at the age above 36 months, particularly to prevent obesity
at the age above 8 years, particularly above 15 years, more
particularly above 18 years.
[0065] Preferably the composition is used to prevent obesity, more
preferably central obesity (i.e. obesity), since especially central
obesity is related to health disorders such as cardiovascular
diseases, hypertension and diabetes.
[0066] In this document and in its claims, the verb "to comprise"
and its conjugations is used in its non-limiting sense to mean that
items following the word are included, but items not specifically
mentioned are not excluded. In addition, reference to an element by
the indefinite article "a" or "an" does not exclude the possibility
that more than one of the element is present, unless the context
clearly requires that there be one and only one of the elements.
The indefinite article "a" or "an" thus usually means "at least
one".
EXAMPLES
Example 1
Programming Effect of Dietary Lipid on Adult Fat Tissue
[0067] Offspring of C57/BL6 dams was standardized on postnatal day
2 to nests of 6 pups (4M and 2F) per dam. Dams were fed the
experimental diet from day 2 onward until weaning. The lipid
composition of the mouse milk reflects the fat composition of the
diet. After weaning the male mice were housed in pairs and the
experimental diet was continued until day 42 when all pups were fed
the same diet containing lard and extra cholesterol (1%).
[0068] The experimental diets that were used were: 1) LC-PUPA diet
(tuna fish oil); 2) Low LA, low LA/ALA diet (butter oil; low in
canola oil, high in Trisun 80, no palm oil); 3) MCFA diet; 4)
control diet (similar amounts of canola oil, coconut oil and palm
oil). The fatty acid composition of the diets is presented in Table
2. At day 42, all mice switched to a "cafeteria diet" comprising 10
wt. % lipid (3 wt. % lard fat and 1 wt. % cholesterol) until day
98. The mice were weighed twice a week. The food intake was
determined once a week during the entire experiment. To determine
body composition (i.e., fat mass (FM) and fat-free mass (FFM)) DEXA
scans (Dual Energy X-ray Absorbiometry) were performed under
general anesthesia at 6, 10 and 14 weeks of age, 42, 70 and 98 days
after birth respectively, by densitometry using a PIXImus imager
(GE Lunar, Madison, Wis., USA). At the age of 14 weeks the male
mice were sacrified and plasma, epididymal fat, renal fat,
pancreas, liver and kidneys were dissected and weighed.
[0069] Results: No effect on growth and food intake was observed
during the experimental period between the groups (data not shown).
Moreover, the development of fat mass (determined with DEXA) was
not different at day 42 (end of the diet intervention period).
However, a subsequent treatment with a cafeteria diet (high in
saturated fatty acids) between day 42 and day 98 of all groups
resulted in clear differences in body composition at the end of the
experiment (day 98), see Table 3. The fat mass was reduced when the
pups received a LC-PUFA, MCFA or low LA, low LA/ALA diet in their
early life, compared to the control diet. Moreover, the diets in
the early life had markedly effect on the body fat distribution. It
was shown that the ratio of the subcutaneous:visceral fat (measured
by epididymal and renal fat, respectively) in adult mice at day 98
was increased by 14% in the LC-PUFA group and 32% in the low LA
group, but was not increased in the MCFA group compared to the
control group, see Table 3. This demonstrated that the visceral fat
mass in later life clearly is decreased by an early in life diet
high in LC-PUFA and/or low in LA and/or low LA/ALA. So, it is
concluded that these fat compositions program and/or imprint the
body to get a healthier body fat composition later-in-life. So, it
is concluded that these fat compositions program and/or imprint the
body to prevent obesity later-in-life.
TABLE-US-00002 TABLE 2 Fatty acid composition of the diets control
MCFA LC-PUFA Low LA Cafetaria g/100 g g/100 g g/100 g g/100 g g/100
g fat fat fat fat fat C-4:0 0.00 0.00 0.00 1.05 0.00 C-6:0 0.11
0.15 0.07 0.81 0.06 C-8:0 1.70 11.42 1.07 2.09 0.85 C-10:0 1.36
8.77 0.86 2.17 0.68 C-12:0 10.53 1.34 6.69 11.42 5.27 C-14:0 4.38
0.75 3.62 7.24 2.69 C-14:1w5 0.00 0.00 0.00 0.00 0.00 C-15:0 0.00
0.00 0.00 0.00 0.00 C-16:0 17.14 13.35 19.38 12.40 23.07 C-16:1w7
0.13 0.12 1.20 0.78 1.56 C-17:0 0.00 0.00 0.37 0.00 0.00 C-18:0
3.07 2.39 3.70 5.12 9.03 C-18:1w9 37.94 38.52 35.27 40.79 40.47
C-18:2w6 LA 14.80 14.31 11.89 6.38 11.90 C-18:3w3 ALA 2.61 2.61
1.07 1.57 1.30 C-18:3w6 0.00 0.00 0.00 0.00 0.00 C-18:4w3 0.00 0.00
0.19 0.00 0.00 C-20:0 0.34 0.34 0.26 0.20 0.17 C-20:1w9 0.41 0.41
0.15 0.22 0.21 C-20:2w6 0.00 0.00 0.00 0.00 0.00 C-20:3w6 0.00 0.00
0.00 0.00 0.00 C-20:4w3 0.00 0.00 0.07 0.00 0.00 C-20:4w6 AA 0.00
0.00 0.28 0.00 0.00 C-20:5w3 EPA 0.00 0.00 1.20 0.00 0.00 C-22:0
0.23 0.28 0.24 0.33 0.11 C-22:1w9 0.14 0.14 0.05 0.08 0.07 C-22:4w6
0.00 0.00 0.00 0.00 0.00 C-22:5w3 DPA 0.00 0.00 0.37 0.00 0.00
C-22:6w3 DHA 0.00 0.00 5.00 0.00 0.00 C-24:0 0.02 0.02 0.02 0.00
0.01 C-24:1w9 0.00 0.00 0.00 0.00 0.00 cholesterol 1.00 total 94.91
94.92 93.02 92.66 98.46
TABLE-US-00003 TABLE 3 Fat % development of total body mass in time
and ratio's of subcutaneous (epididymal) and central (renal) fat.
Control MCFA LC-PUFA Low LA Day diet diet diet diet Fat mass (%) 42
19.6 17.1 16.6 17.1 Fat mass (%) 70 22.1 22.8 21.5 24.2 Fat mass
(%) 98 26.9 22.8 20.9 24.2 Ratio subcutaneous 98 7.54 7.2 8.59 9.92
fat/visceral fat Ratio increase (%) -4% +14% +32%
Example 2
Phospholipids Beneficially Affect Insulin Sensitivity
[0070] Nutritional compositions: A complete infant formula with
extra added phospholipids (0.2 g/100 ml) was manufactured using a
commercially available buttermilk/butterserum concentrate of
Lactalis as source. An infant formula with a comparable
composition, but without added phospholipids was used as control.
The concentration of added phospholipids was about 6.3 wt. % based
on total lipid in the experimental formula and about 0.75 wt. %
based on total lipid in the control formula. The experimental
composition comprised about 1.4 wt. % sphingomyelin based on total
lipid and about 4 wt. % cholesterol based on total lipid. The
amount of sphingomyelin and cholesterol was negligible in the
control formula.
[0071] Methods: 20 adult male Wistar rats (aged 10 weeks at the
start of the experiment) were housed individually. After a 4 h
fasting period, 10 animals were fed 2 ml of a composition. Three
different compositions were tested in a cross-over design
(experiments separated by one week) i) Standard infant formula, ii)
Phospholipid comprising formula. Subsequently, blood samples (200
.mu.l) were collected in heparinised chilled tubes at t=0, 5, 10,
15, 30, 60 after feeding. Subsequently, plasma was separated after
centrifugation (10 min, 5000 rpm) and stored at -20.degree. C.
until analysis. Plasma insulin was measured by radioimmunoassay
(RIA, of Linco Research) according to the manufacturer's
instructions with the following adjustment: all assay volumes were
reduced four times.
[0072] Results: The area under the curve (AUC) of insulin was lower
in rats fed phospholipid containing formula than in rats fed with
standard formula. (Table 4). Administration of a phospholipid,
sphingolipid and/or cholesterol comprising formula resulted in
post-prandial insulin levels and kinetics more similar to those
previously observed with human milk. Decreased levels of insulin
indicate increased insulin sensitivity, which is believed
contribute to the prevention of obesity, especially central
obesity, later-in-life.
TABLE-US-00004 TABLE 4 Effects of phospholipids on post-prandial
area under the curve of insulin. Effect Standard Phospholipids
Human milk AUC 10 ( .+-.SE) Insulin (pM*10 min) 9.8 .+-. 1.4 9.5
.+-. 1.0 AUC 15 ( .+-.SE) Insulin (pM*15 min) 14.8 .+-. 2.1 13.8
.+-. 1.6 AUC 30 ( .+-.SE) Insulin (pM*30 min) 21.4 .+-. 2.9 18.7
.+-. 2.0 11.7 .+-. 4.7 AUC 60 ( .+-.SE) Insulin (pM*60 min) 25.8
.+-. 3.3 23.6 .+-. 2.2
Example 3
Blood Glucose/Insulin and Non-Digestible Oligosaccharides
[0073] Animals and treatment: Adult male Wistar rats (n=7) were
given a GOS fiber load, cellulose load or water via a gastric
canula on day 1. A 6 ml bolus load was administered equal to 50% of
their daily fiber intake; GOS fiber used was
transgalacto-oligosaccharides obtained from Elix'or (Borculo Domo).
Fiber was dissolved in water. About 24 h later (on day 2) an oral
glucose tolerance test was carried out and the postprandial glucose
and insulin course was monitored for 120 min upon the intragastric
injection of a carbohydrate load (2 g/kg body weight). To this end
blood samples were drawn repeatedly via a jugular vein canula.
Intragastric injection of water or a cellulose solution in water on
day 1 served as control. As the GOS fiber preparation consisted of
50% of digestible carbohydrates (mainly lactose), the two control
injections were co-administered with carbohydrates to correct for
this.
[0074] Results: pre-treatment with GOS fibers clearly decreased the
amount of insulin secreted, resulting in significant (p<0.05)
lower incremental AUC values. Blood glucose levels were not
affected significantly. Pre-treatment with cellulose or water did
not modulate the insulin secretion, see Table 5.
TABLE-US-00005 TABLE 5 Insulin and glucose levels in rats. AUC
insulin AUC glucose Pre-treatment with: (pM*30 min) (mM*30 min)
Water 41 .+-. 7 69 .+-. 10 Cellulose 46 .+-. 8 75 .+-. 9 GOS 22
.+-. 4 74 .+-. 15
Example 4
Infant Nutrition
[0075] Infant nutrition comprising a lipid component providing 48%
of the total calories, a protein component providing 8% of the
total calories and a digestible carbohydrate component providing
44% of the total calories; (i) the lipid component comprising based
on total fatty acids: 14 wt. % LA; 2.6 wt. % ALA, 3.7 wt. % MCFA;
0.2 wt. % DHA, 0.05 wt. % EPA; 0.02 wt. % DPA, 0.35 wt. % AA, 0.03
wt. % DHGLA. Based on total fat the composition comprises about
0.75 wt. % soy phospholipids and >0.005 wt. % cholesterol. (ii)
the carbohydrate component comprising 50.9 gram lactose/100 gram
powder; 5.22 g galacto-oligosaccharides with DP 2-6 and 0.58 g
fructo-oligosaccharides with DP 7-60; (ii) the protein component
comprising cow milk protein, including casein. Furthermore the
composition comprises 73 mg choline and 5.6 mg UMP per 100 g dry
weight. The composition comprises 364 mg calcium per 100 g dry
weight. The composition comprises vitamins and minerals according
to EU guidelines. The label of the package of this infant nutrition
indicates that the nutrition prevents the development of
obesity.
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