FIELD OF THE INVENTION

The present invention relates to a nutritional composition for infants at risk of a disadvantageous body composition development or at risk of becoming obese (for example due to being born to a mother that developed gestational diabetes) for use in improving body composition and/or reducing the risk and/or severity of obesity of such infants.

BACKGROUND OF THE INVENTION Human milk is the uncontested gold standard concerning infant nutrition. However, in some cases breastfeeding is inadequate or unsuccessful for medical reasons or because of a choice not to breastfeed. For such situations infant or follow-on formulas have been developed. Commercial infant formulas are commonly used today to provide supplemental or sole source of nutrition early in life. These formulas comprise a range of nutrients to meet the nutritional needs of the growing infant, and typically include fat, carbohydrate, protein, vitamins, minerals, and other nutrients helpful for optimal infant growth and development. Commercial infant formulas are designed to mimic, as closely as possible, the composition and function of human milk.

Gestational diabetes mellitus (GDM) is a serious health condition that arises during pregnancy. It is characterized by hyperglycemia during pregnancy and results in short- and long-term consequences for the mother and child. Notably, infants born from a GDM pregnancy have an increased risk of overweight and obesity in infancy, childhood and in later life (Logan et al Arch Dis Child Fetal Neonatal Ed 2017;102:F65-F72; Farahvar et al Expert Review of Endocrinology & Metabolism, 2018, 14(1):63-74; Nijs and Benhalima J Clin Med 2020, 9, 599; doi:10.3390/ jcm9020599). Current treatment options are limited and focus mainly on diet and lifestyle interventions or insulin therapy for the pregnant women, yet these options do not appear to decrease the longer term risks such as developing a disadvantageous body composition, in particular with regard to fat mass and lean body mass, for their children. In WO 2017/064309 it is disclosed that infant formula comprising a lipid component in the form of a mixture of vegetable fats and bovine milk fat promoted a postnatal growth trajectory or body development in an infant that was more similar to that of human milk fed infants.

WO 2013/191533 relates to infant formulas comprising vegetable fat and mammalian milk fat and having large lipid globules that preferably also have phospholipids in the outer layer of the lipid globules for the prevention of obesity later in life and the improvement of body composition. These infants were born from healthy mothers and were preterm/small for gestational age that often encounter catch up growth early in life. Similarly, US 2016/0081963 describes an infant formula for infants born from healthy mothers to prevent/reduce obesity later in life wherein the infant formula comprises at least 10 wt. % palmitic acid based on total fatty acids, wherein at least 30 wt. % of the palmitic acid is esterified to the sn- 2 position of a triglyceride based on total palmitic acid.

US 2016/219915 involves a composition comprising large lipid globules containing vegetable fat as the lipid ingredient which are coated with phospholipids and polar lipids for improving body composition later in life in infants born from a mother with diabetes/obesity. Non pre-published WO 2021/110916 describes that infants born from overweight or obese mothers receiving an infant formula comprising a mix of vegetable fat and milk fat improves the growth trajectory or body development in terms of the Body Mass Index (BMI).

SUMMARY OF THE INVENTION The present inventors have surprisingly found that the consumption of a nutritional composition comprising a mixture of vegetable fat and milk fat beneficially affects the body composition in subjects at risk of developing a disadvantageous body composition.

A mouse model was used, wherein a GDM-like phenotype (gestational diabetes mellitus) was induced in dams by feeding them a high-fat diet (to reduce insulin sensitivity) and exposing them to three mild streptozotocin triggers (to reduce beta cell capacity). The offspring of these GDM dams were fed in early life either with a nutritional composition according to the invention, i.e. a nutritional composition comprising a mixture of vegetable fat and milk fat, or a control nutritional composition comprising mainly vegetable fat. Offspring of GDM dams are more at risk of overweight and obesity and thus developing a disadvantageous body composition. After exposure to a Western style diet (WSD) later in life, the body weight of the offspring fed with either nutritional composition early in life were not significantly different. However, the offspring fed the nutritional composition according to the invention unexpectedly developed a significantly reduced level of fat mass and percentage of fat mass and significantly increased level of lean body mass compared to the offspring that was fed the control nutritional composition. This is indicative that consumption in early life of the nutritional composition according to the invention improves body composition in infants at risk of developing a disadvantageous body composition and reduces the risk and/or severity of obesity in at risk infants. Since the overall fatty acid composition in the diets was very similar, the observed reduction in fat mass and relative fat mass was wholly unexpected, all the more since the diet later in life for both groups was the same obesogenic Western style diet. Thus, due to the presence in the early life diet of a mixture of vegetable fat and milk fat, this early life diet was able to program differences in body composition development which results in a healthier body composition and reduced risk of becoming obese later in life, i.e. adulthood. The present invention hence relates to nutritional compositions, in particular formulae for infants or growing up milks for toddlers, comprising a mixture of vegetable fat and milk fat that can be used to improve body composition and reduce the risk of obesity and/or reduce severity of obesity in infants at risk of developing a disadvantageous body composition and/or becoming obese, for example due to being born to a mother that developed gestational diabetes.

DETAILED DESCRIPTION OF THE INVENTION

The present invention thus pertains to a nutritional composition selected from infant formula, follow- on formula and young child formula, comprising digestible carbohydrates, protein and lipid, wherein the lipid comprises i) 30 to 90 wt% vegetable lipid based on total lipid, ii) 10 to 70 wt% based on total lipid of mammalian milk lipid derived from the group consisting of butter, butter fat, butter oil and anhydrous milk fat for use in improving body composition in a human subject selected from the group consisting of an infant born to an overweight and/or obese mother at the time of conception of the infant; an infant born to a mother with diabetes at the time of conception of the infant; - an infant born to a mother with gestational diabetes (GDM); and an infant who was large for its gestational age (LGA) at birth.

The present invention also pertains to a nutritional composition selected from infant formula, follow- on formula and young child formula, comprising digestible carbohydrates, protein and lipid, wherein the lipid comprises i) 30 to 90 wt% vegetable lipid based on total lipid, ii) 10 to 70 wt% based on total lipid of mammalian milk lipid derived from the group consisting of butter, butter fat, butter oil and anhydrous milk fat for use in reducing the risk of obesity and/or reducing severity of obesity in a human subject selected from the group consisting of an infant born to an overweight and/or obese mother at the time of conception of the infant; an infant born to a mother with diabetes at the time of conception of the infant; an infant born to a mother with gestational diabetes (GDM); and - an infant who was large for its gestational age (LGA) at birth.

For some jurisdictions, the invention can also be worded as the use of digestible carbohydrates, protein and lipid in the manufacture of a nutritional composition, selected from infant formula, follow- on formula and young child formula, for improving body composition in a human subject selected from the group consisting of an infant born to an overweight and/or obese mother at the time of conception of the infant; an infant born to a mother with diabetes at the time of conception of the infant; an infant born to a mother with gestational diabetes (GDM); and - an infant who was large for its gestational age (LGA) at birth wherein the lipid comprises i) 30 to 90 wt% vegetable lipid based on total lipid, ii) 10 to 70 wt% based on total lipid of mammalian milk lipid derived from the group consisting of butter, butter fat, butter oil and anhydrous milk fat.

Likewise, for some jurisdictions, the invention can also be worded as the use of digestible carbohydrates, protein and lipid in the manufacture of a nutritional composition, selected from infant formula, follow-on formula and young child formula, for reducing the risk of obesity and/or reducing severity of obesity in a human subject selected from the group consisting of - an infant born to an overweight and/or obese mother at the time of conception of the infant; an infant born to a mother with diabetes at the time of conception of the infant; an infant born to a mother with gestational diabetes (GDM); and an infant who was large for its gestational age (LGA) at birth wherein the lipid comprises i) 30 to 90 wt% vegetable lipid based on total lipid, ii) 10 to 70 wt% based on total lipid of mammalian milk lipid derived from the group consisting of butter, butter fat, butter oil and anhydrous milk fat. For some jurisdictions, the invention can also be worded as a method for improving body composition in a human subject selected from the group consisting of an infant born to an overweight and/or obese mother at the time of conception of the infant; an infant born to a mother with diabetes at the time of conception of the infant; - an infant born to a mother with gestational diabetes (GDM); and an infant who was large for its gestational age (LGA) at birth said method comprising feeding said human subject a nutritional composition, selected from infant formula, follow-on formula and young child formula, said nutritional composition comprising digestible carbohydrates, protein and lipid, wherein the lipid comprises i) 30 to 90 wt% vegetable lipid based on total lipid, ii) 10 to 70 wt% based on total lipid of mammalian milk lipid derived from the group consisting of butter, butter fat, butter oil and anhydrous milk fat. Likewise, for some jurisdictions, the invention can also be worded as a method for reducing the risk of obesity and/or reducing severity of obesity in a human subject selected from the group consisting of an infant born to an overweight and/or obese mother at the time of conception of the infant; an infant born to a mother with diabetes at the time of conception of the infant; an infant born to a mother with gestational diabetes (GDM); and an infant who was large for its gestational age (LGA) at birth said method comprising feeding said human subject a nutritional composition, selected from infant formula, follow-on formula and young child formula, said nutritional composition comprising digestible carbohydrates, protein and lipid, wherein the lipid comprises i) 30 to 90 wt% vegetable lipid based on total lipid, ii) 10 to 70 wt% based on total lipid of mammalian milk lipid derived from the group consisting of butter, butter fat, butter oil and anhydrous milk fat.

In some jurisdictions administering a nutritional composition to an infant is considered non- therapeutic. In those instances the invention can be worded as defined above by way of a method comprising administering a nutritional composition. For clarity, the method can also be defined as a non-therapeutic method for improving body composition or reducing the risk of obesity or reducing severity of obesity in an infant as defined above. By definition, the words “non-therapeutic” exclude any therapeutic effect.

In the context of the present invention, the infant formula or follow-on formula is not native cow’s milk or human milk.

In the context of the present invention, young child formula can also be named growing-up milk.

In the context of the present invention a motherthat is overweight or obese at the time of conception of the infant is based on the BMI of the mother before pregnancy. In one embodiment, the BMI before pregnancy is defined as the BMI as measured in the time period at least six months before conception.

In this specification, the following terms have the meanings assigned to them here below (Chiu M etal. Diabetes Care, 2011 , 34:1741-1748):

The term ‘BMI’ as used herein, is defined as the body mass divided by the square of the body height, and is expressed in units of kg/m ² . The BMI broadly categorizes a person as underweight, normal weight, overweight, or obese according to the calculated BMI value. The terms ‘underweight’, ‘normal weight’, ‘overweight’ and ‘obese’ as herein are defined as follows: Underweight is defined as a BMI < 18.5 kg/m2 for all women. A normal weight for Asian women is considered a BMI >18.5 and <23 kg/m2, for non-Asian women, a normal weight is a BMI >18.5 and <25 kg/m2. Overweight for Asian women is considered a BMI > 23 and < 27.5 kg/m2, for non-Asian women, overweight is a BMI > 25 and <30 kg/m2. Obese for Asian women is considered a BMI > 27.5 kg/m2, for non-Asian women, obese is a BMI > 30 kg/m2.

In the context of the present invention a ‘mother with diabetes at the time of conception’ is a mother who has been diagnosed by a health care professional with diabetes mellitus type 1 or diabetes mellitus type 2. In the context of this invention this diagnosis of diabetes mellitus type 1 or 2 was made by a health care professional at the latest at the end of the 1 ^st trimester during the pregnancy of the infant. Preferably the mother with diabetes at the time of conception is a mother with diabetes mellitus type 2. In the context of the present invention a ‘mother with gestational diabetes’ is a mother who has been diagnosed by a health care professional to suffer from gestational diabetes mellitus (GDM) during pregnancy. In the context of the present invention the GDM diagnosis is preferably based on IADPSG criteria (IADPSG: International Association of Diabetes and Pregnancy Study Group). Typically, a GDM diagnosis is made at the earliest in the second trimester during pregnancy. GDM occurs in pregnant women without a previous history of diabetes and is transient, i.e. the pathology disappears when the woman is not pregnant anymore.

In the context of the present invention ‘an infant who was large for its gestational age (LGA) at birth’ is an infant with a weight, length, or head circumference at birth that lies above the 90th percentile for that gestational age. Both infants born to women with pre-pregnancy overweight or obesity and infants born to women with diabetes (diabetes mellitus type 1 , diabetes mellitus type 2 or GDM) have a higher risk of being LGA.

The unifying concept between these sub-groups is that all these infants are or have a higher risk of being exposed in utero to increased levels of glucose compared to infants born from healthy mothers. Exposure to increased levels of glucose or hyperglycaemia lead to both short- as well as long-term effects in the infant. The long-term effects may comprise increased risk of developing obesity and/or cardiovascular diseases in later life and neurodevelopmental problems in early life. The most predominant effect is the development of a disadvantageous body composition with regard to an increased or higher than normal fat mass.

Throughout this description, lipid and fat are used interchangeably. Application

According to the present invention, the human subject is selected from the group consisting of an infant born to an overweight and/or obese mother at the time of conception of the infant; an infant born to a mother with diabetes at the time of conception of the infant; - an infant born to a mother with GDM; and an infant who was LGA at birth.

The infants listed here above are all considered by the skilled person to be populations at risk of developing a disadvantageous body composition later in life and/or at risk of becoming obese later in life.

In a preferred embodiment the human subject is selected from the group consisting of an infant born to an overweight and/or obese mother at the time of conception of the infant; an infant born to a mother with diabetes at the time of conception of the infant; and an infant born to a mother with GDM.

In a more preferred embodiment the human subject is selected from the group consisting of: an infant born to a mother with diabetes at the time of conception of the infant; and an infant born to a mother with GDM. In an even more preferred embodiment the human subject is an infant born to a mother with GDM.

In an even more preferred embodiment the human subject is an infant born to an overweight and/or obese mother at the time of conception of the infant and wherein the mother also has GDM. According to the present invention the body composition of the above defined ‘at risk’ infants is improved. Also, according to the present invention the risk of obesity of the above defined ‘at risk’ infants is reduced and/or the severity of obesity of the above defined ‘at risk’ infants is reduced. The improvement in body composition or the reduction of the risk of obesity or the reduction of the severity of obesity is compared to the body composition or the risk of obesity or the severity of obesity of the same ‘at risk’ infants who did not consume the nutritional composition comprising a mixture of vegetable fat and milk fat but instead consumed a standard or control nutritional composition. The standard or control nutritional composition is characterised by comprising at least 95 wt% vegetable lipid based on total lipid and less than 2 wt% based on total lipid of mammalian milk lipid derived from the group consisting of butter, butter fat, butter oil and anhydrous milk fat.

Thus in a preferred embodiment according to the invention, improving body composition or reducing the risk of obesity or reducing the severity of obesity is compared to the body composition or the risk of obesity or severity of obesity of a human subject fed a nutritional composition, selected from infant formula, follow-on formula and young child formula, comprising digestible carbohydrates, protein and lipid, said nutritional composition comprising at least 95 wt% vegetable lipid based on total lipid and less than 2 wt% based on total lipid of mammalian milk lipid derived from the group consisting of butter, butter fat, butter oil and anhydrous milk fat.

For a proper comparison, the standard or control nutritional composition is fed to a human subject from the same group and is of the same age and is fed for the same period of time.

In a preferred embodiment according to the invention, improving body composition is selected from one or more of the group consisting of reducing fat mass, increasing lean body mass and reducing the percentage of fat mass, preferably improving body composition is reducing the percentage of fat mass. In this embodiment, improving body composition is not the same as improving body development or growth trajectory in which weight is compared to length (BMI). It may still be that infants having average weights versus average lengths and consequently an average BMI nevertheless have an increased fat mass or a lowered lean body mass and thus a disadvantageous body composition. Hence, in a preferred embodiment, improving body composition means most importantly that the ratio of fat mass to lean mass is reduced later in life. Preferably, the percentage of fat mass is reduced later in life by at least 20%, more preferably by at least 30%, even more preferably the percentage of fat mass to lean mass is reduced by at least 40%, most preferably by at least 50% compared to subjects given an infant milk formula (IMF) comprising predominantly vegetable fat.

Preferably the one or more above body composition improvements is established after the administration of the nutritional composition has stopped. In other words, preferably the one or more above body composition improvements is established later in life. Thus in a further preferred embodiment according to the invention, improving body composition is reducing the percentage of fat mass later in life.

In a preferred embodiment, the human subject is exposed to a Western style diet later in life. In yet a further preferred embodiment according to the invention, improving body composition or reducing the risk of obesity or reducing severity of obesity is later in life upon exposure to a Western style diet.

A Western-style diet is known in the art to be a general unhealthy diet, characterized by a large content of (unhealthy) lipids and a large content of rapidly digestible carbohydrates, in particular sucrose. A Western-style diet may also be referred to as a “high-fat diet”, as a “cafeteria diet” or as “unhealthy diet”. Typically, a Western-style diet is high in fat and high in saturated fat. In the context of the present invention, the Western-style diet is defined as containing more than 45 % lipid, based on total calories of the daily food intake, wherein the lipid contains at least 50 % by weight of saturated fats, such as present in for example cream, cheese, butter, ghee, suet, tallow, lard, and fatty meats. Further, the Western-style diet is defined as containing more than 50 % carbohydrate, based on total calories of the daily food intake, wherein the carbohydrate contains at least 75 % by weight of rapidly digestible carbohydrates selected from the group consisting of glucose, fructose, sucrose, lactose and starch.

Lipid The nutritional composition for use according to the present invention comprises lipid. Lipid in the present invention comprises one or more selected from the group consisting of triglycerides, polar lipids (such as phospholipids, cholesterol, glycolipids, sphingomyelin), free fatty acids, monoglycerides and diglycerides. Preferably the composition comprises at least 70 wt%, more preferably at least 80 wt%, more preferably at least 85 wt% triglycerides, even more preferably at least 90 wt% triglycerides based on total lipid.

The lipid provides preferably 30 to 60 % of the total calories of the nutritional composition. More preferably the nutritional composition comprises lipid providing 35 to 55 % of the total calories, even more preferably the nutritional composition comprises lipid providing 40 to 50 % of the total calories. The lipid is preferably present in an amount of 3 to 7 g per 100 kcal, more preferably in an amount of 4 to 6 g lipid per 100 kcal and most preferably in an amount of 4.5 to 5.5 g lipid per 100 kcal. When in liquid form, e.g. as a ready-to-feed liquid, the nutritional 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 nutritional composition preferably comprises 10 to 50 wt%, more preferably 12.5 to 40 wt% lipid, even more preferably 19 to 30 wt% lipid.

The lipid comprises vegetable lipid. The presence of vegetable lipid advantageously enables an optimal fatty acid profile high in polyunsaturated fatty acids and/or more reminiscent to human milk fat. Lipid from non-human mammalian milk alone, e.g. cow’s milk, does not provide an optimal fatty acid profile. The amount of essential fatty acids is too low in non-human mammalian milk.

Preferably the nutritional composition comprises at least one, preferably at least two vegetable lipid sources selected from the group consisting of linseed oil (flaxseed oil), rape seed oil (such as colza oil, low erucic acid rape seed oil and canola oil), sunflower oil, high oleic sunflower oil, safflower oil, high oleic safflower oil, olive oil, coconut oil, palm oil and palm kernel oil.

In a preferred embodiment, the nutritional composition comprises 30 to 90 wt% vegetable lipid based on total lipid, more preferably 35 to 80 wt%, more preferably 40 to 70 wt%, more preferably 40 to 60 wt% vegetable lipid based on total lipid.

The lipid in the nutritional composition for the use according to the invention further comprises lipid from mammalian milk, preferably ruminants milk, preferably cow's milk, goat milk, sheep milk, buffalo milk, yak milk, reindeer milk, and camel milk, most preferably cow's milk. Preferably the mammalian milk is not human milk. Preferably the mammalian milk component comprises at least 70 wt% triglycerides, more preferably at least 90 wt, more preferably at least 97 wt%. Preferably the mammalian milk lipid is derived from the group consisting of butter, butter fat, butter oil, and anhydrous milk fat, more preferably anhydrous milk fat and butter oil. Such milk fat lipid sources are high in triglyceride levels. Furthermore these lipid sources are in the form of a continuous fat phase or a water-in-oil emulsion form. Using these sources of milk fat during the manufacture of the nutritional composition of the present invention enable the formation of lipid globules, wherein each globule comprising a mixture of vegetable fat and milk fat. When milk fat sources are used which are an oil-in-water emulsion, lipid globules being either composed of milk fat or composed of vegetable fat will be generated, which are believed to be less effective.

Milk fat in the present invention refers to all lipid components of milk, as produced by the mammalians, such as the cow, and is found in commercial milk and milk-derived products.

Butter in the present invention is a water-in-oil emulsion comprised of over 80 wt% milk fat.

Butterfat in the present invention relates to all of the fat components in milk that are separable by churning, in other words, present in butter.

Anhydrous milk fat (AMF) is a term known in the art and relates to extracted milk fat. Typically AMF comprises more than 99 wt% lipid based on total weight. It can be prepared from extracting milk fat from cream or butter. Anhydrous butter oil in the present invention is synonymous with AMF.

Butteroil also is a term known in the art. It typically relates to a milk lipid extract with more than 98 wt% lipid and typically is a precursor in the process of preparing anhydrous milk fat or anhydrous butter oil.

Preferably the composition comprises 10 to 70 wt% milk lipid based on total lipid, more preferably 20 to 65 wt%, more preferably 30 to 60 wt%, more preferably 40 to 60 wt% based on total lipid. Preferably the milk lipid is selected from the group consisting of butter, butter fat, butter oil, and anhydrous milk fat.

Preferably the ratio of vegetable fat to milk fat ranges from 3/7 to 9/1 .

In a preferred embodiment, the lipid in the nutritional composition comprises: a) 35 to 80 wt% vegetable lipid based on total lipid, and b) 20 to 65 wt% mammalian milk fat based on total lipid, wherein the mammalian milk fat is selected from butter, butter fat, butter oil or anhydrous milk fat. More preferably, the lipid in the nutritional composition comprises: a) 40 to 70 wt% vegetable lipid based on total lipid, and b) 30 to 60 wt% mammalian milk fat based on total lipid, wherein the mammalian milk fat is selected from butter, butter fat, butter oil or anhydrous milk fat. Most preferably, the lipid in the nutritional composition comprises: a) 40 to 60 wt% vegetable lipid based on total lipid, and b) 40 to 60 wt% mammalian milk fat based on total lipid, wherein the mammalian milk fat is selected from butter, butter fat, butter oil or anhydrous milk fat. The nutritional composition also may comprise non-vegetable lipid and non-milk fat, such as animal fat other than milk fat, such as fish oil, and egg lipid, and microbial, algal, fungal or single cell oils. Preferably the non-vegetable, non-milk fat is present in an amount of at most 10 wt% based on total lipid, more preferably at most 5 wt%. Preferably the lipid in the nutritional composition comprises a fat source comprising long chain poly-unsaturated fatty acids (LC-PUFA), selected from the group consisting of fish oil, marine oil, algal oil, microbial oil, single cell oil and egg lipid in an amount of 0.25 to 10 wt% based on total lipid, preferably in an amount of 0.5 to 10 wt%.

Compared to vegetable fat, milk fat is known to have a higher content of palmitic acid (PA) at the sn-2 position of a triglyceride. In a preferred embodiment, the lipid in the nutritional composition for use according to the invention comprises at least 10 wt% palmitic acid (PA) based on total fatty acids and at least 15 wt% of palmitic acid, based on total palmitic acid, is located at the sn-2 position of a triglyceride. Preferably the amount of PA that is present is below 30 wt% based on total fatty acids. More preferably the amount of PA that is present in the lipid is from 12 to 26 wt% based on total fatty acids in the total lipid, even more preferably from 14 to 24 wt%.

The lipid in the nutritional composition is preferably chosen such that, based on the total PA present in the lipid, at least 15 wt%, preferably at least 20 wt%, more preferably at least 25 wt%, more preferably at least 30 wt% PA is in the sn-2 or beta position in a triglyceride. Preferably the amount of PA in the sn-2 position in a triglyceride is not more than 45 wt%, preferably not more than 40 wt% based on total PA present in the lipid. Preferably the amount of PA in the sn-2 position in a triglyceride is from 25 to 40 wt% based on total PA present in the total lipid.

Compared to vegetable fat, milk fat is known to have a higher content of short-chain fatty acids butyric acid (BA; C4) and caproic acid (CA; C6). In a preferred embodiment, the lipid in the nutritional composition for use according to the invention comprises 0.6 to 5 wt% short chain fatty acids (SCFA) being the sum of butyric acid (BA) and caproic acid (CA) based on total fatty acids. Preferably the nutritional composition comprises less than 5 wt% BA based on total fatty acids, preferably less than 4 wt%. Preferably the nutritional composition comprises at least 0.5 wt% butyric acid based on total fatty acids, preferably at least 0.6 wt%, preferably at least 0.9 wt%, more preferably at least 1 .2 wt% BA based on total fatty acids. In a preferred embodiment, the lipid in the nutritional composition for use according to the invention comprises at least 10 wt% palmitic acid based on total fatty acids and at least 15 wt% of palmitic acid, based on total palmitic acid, is located at the sn-2 position of a triglyceride and comprises 0.6 to 5 wt% short chain fatty acids (SCFA) being the sum of butyric acid (BA) and caproic acid (CA) based on total fatty acids.

Faty acid composition

SFA relates to saturated fatty acids and/or acyl chains, MUFA relates to mono-unsaturated fatty acid and/or acyl chains, PUFA refers to polyunsaturated fatty acids and/or acyl chains with 2 or more unsaturated bonds; 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; Medium chain fatty acids (MCFA) refer to fatty acids and/or acyl chains with a chain length of 6, 8 or 10 carbon atoms. n3 or omega-3 PUFA refers to polyunsaturated fatty acids and/or acyl chains with 2 or more unsaturated bonds with an unsaturated bond at the third carbon atom from the methyl end of the fatty acyl chain, n6 or omega-6 PUFA refers to polyunsaturated fatty acids and/or acyl chains with 2 or more unsaturated bonds with an unsaturated bond at the sixth carbon atom from the methyl end of the fatty acyl chain. DHA refers to docosahexaenoic acid and/or acyl chain (22:6, n3); DPA refers to docosapentaenoic acid and/or acyl chain (22:5 n3). EPA refers to eicosapentaenoic acid and/or acyl chain (20:5 n3); ARA refers to arachidonic acid and/or acyl chain (20:4 n6). LA refers to linoleic acid and/or acyl chain (18:2 n6); ALA refers to alpha-linolenic acid and/or acyl chain (18:3 n3). PA relates to palmitic acid and/or acyl chains (C16:0). BA refers to butyric acid (C4:0). CA refers to caproic acid (C6:0).

LA refers to linoleic acid and/or acyl chain and is an n6 PUFA (18:2 n6) and the precursor of n6 LC- PUFA and is an essential fatty acid as it cannot be synthesized by the human body. The nutritional composition according to the present use preferably comprises linoleic acid (LA). LA preferably is present in a sufficient amount in order to promote a healthy growth and development, yet in an amount as low as possible to prevent negative, competitive, effects on the formation of n3 PUFA and a too high n6/n3 ratio. The nutritional composition therefore preferably comprises less than 20 wt% LA based on total fatty acids, preferably 5 to 16 wt%, more preferably 10 to 14.5 wt%. Preferably, the nutritional composition comprises at least 5 wt% LA based on total fatty acids, preferably at least 6 wt% LA, more preferably at least 7 wt% LA based on total fatty acids.

ALA refers to a-linolenic acid and/or acyl chain and is an n3 PUFA (18:3 n3) and the precursor of n3 LC-PUFA and is an essential fatty acid as it cannot be synthesized by the human body. The nutritional composition according to the present use preferably comprises ALA. Preferably ALA is present in a sufficient amount to promote a healthy growth and development of the infant. The nutritional composition therefore preferably comprises at least 1.0 wt%, more preferably the nutritional composition comprises at least 1.5 wt%, even more preferably at least 2.0 wt% ALA based on total fatty acids. Preferably the nutritional composition comprises less than 10 wt% ALA, more preferably less than 5.0 wt% based on total fatty acids. Preferably the nutritional composition comprises a weight ratio of LA/ALA from 2 to 20, more preferably from 3 to 16, more preferably from 4 to 14, more preferably from 5 to 12.

The lipid that is present in the nutritional composition for use according to the invention preferably comprises 5 to 35 wt% poly-unsaturated fatty acids (PUFA), based on total fatty acids, comprising linoleic acid (LA) and alpha-linolenic acid (ALA) in a weight ratio LA/ALA of 2 to 20.

Preferably, the nutritional composition comprises n3 LC-PUFA, such as EPA, DPA and/or DHA, more preferably DHA. As the conversion of ALA to DHA may be less efficient in infants, preferably both ALA and DHA are present in the nutritional composition. Preferably the nutritional composition comprises at least 0.05 wt%, preferably at least 0.1 wt%, more preferably at least 0.2 wt%, of DHA based on total fatty acids. Preferably the nutritional composition comprises not more than 2.0 wt%, preferably not more than 1.0 wt% of DHA based on total fatty acids.

The nutritional composition in one embodiment comprises ARA. Preferably the nutritional composition comprises at least 0.05 wt%, preferably at least 0.1 wt%, more preferably at least 0.2 wt% of ARA based on total fatty acids. As the group of n6 fatty acids, especially arachidonic acid (ARA) counteracts the group of n3 fatty acids, especially DHA, the nutritional composition preferably comprises relatively low amounts of ARA. Preferably the nutritional composition comprises not more than 2.0 wt%, preferably not more than 1.0 wt% of ARA based on total fatty acids. Preferably the weight ratio between DHA and ARA is between 1 :4 to 4:1 , more preferably between 1 :2 to 2:1 , more preferably between 0.6 and 1.5. ARA may also be absent.

Digestible carbohydrates

The nutritional composition comprises digestible carbohydrates. The digestible carbohydrates preferably provide 25 to 75% of the total calories of the nutritional composition. Preferably the digestible carbohydrates provide 40 to 60% of the total calories. Based on calories the nutritional composition preferably comprises of 5 to 20 g of digestible carbohydrates per 100 kcal, more preferably 6 to 16 g per 100 kcal. When in liquid form, e.g. as a ready-to-feed liquid, the nutritional composition preferably comprises 3 to 30 g digestible carbohydrate per 100 ml, more preferably 6 to 20, even more preferably 7 to 10 g per 100 ml. Based on dry weight the nutritional composition preferably comprises 20 to 80 wt%, more preferably 40 to 65 wt% digestible carbohydrates.

Preferred digestible carbohydrate sources are lactose, glucose, sucrose, fructose, galactose, maltose, starch and maltodextrin. Lactose is the main digestible carbohydrate present in human milk. Lactose advantageously has a low glycaemic index. The nutritional composition preferably comprises lactose. The nutritional composition preferably comprises digestible carbohydrate, 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% of the digestible carbohydrate is lactose. Based on dry weight the nutritional composition preferably comprises at least 25 wt% lactose, preferably at least 40 wt% lactose.

Protein

The nutritional composition comprises protein. The protein preferably provides 5 to 20% of the total calories. Preferably the nutritional composition comprises protein that provides 6 to 12% of the total calories. Preferably the nutritional composition comprises less than 3.5 g protein per 100 kcal, more preferably the nutritional composition comprises between 1.5 and 2.1 g protein per 100 kcal, even more preferably between 1.6 and 2.0 g protein per 100 kcal. A low protein concentration advantageously is closer to human milk as human milk comprises a lower amount of protein based on total calories compared to cow’s milk. The protein concentration in a nutritional composition is determined by the sum of protein, peptides and free amino acids. Based on dry weight the nutritional composition preferably comprises less than 12 wt% protein, more preferably between 9.6 and 12 wt%, even more preferably between 10 and 11 wt%. Based on a ready-to-drink liquid product the nutritional composition preferably comprises less than 1.5 g protein per 100 ml, more preferably between 1 .2 and 1 .5 g, even more preferably between 1 .25 and 1 .35 g per 100 ml.

The source of the protein should be selected in such a way that the minimum requirements for essential amino acid content are met and satisfactory growth is ensured. Hence protein sources based on cows' milk proteins such as whey, casein and mixtures thereof and proteins based on soy, potato or pea are preferred. In case whey proteins are used, the protein source is preferably based on acid whey or sweet whey, whey protein isolate or mixtures thereof. Preferably the nutritional composition comprises at least 3 wt% casein based on dry weight. Preferably the casein is intact and/or non-hydrolyzed.

Non-diaestible carbohydrates In one embodiment the nutritional composition preferably comprises non-digestible oligosaccharides. Preferably the nutritional composition comprises non-digestible oligosaccharides with a degree of polymerization (DP) between 2 and 250, more preferably between 3 and 60.

Preferably the nutritional composition comprises fructo-oligosaccharides, galacto-oligosaccharides and/or galacturonic acid oligosaccharides, more preferably fructo-oligosaccharides and/or galacto- oligosaccharides, even more preferably galacto-oligosaccharides, most preferably transgalacto- oligosaccharides. In a preferred embodiment the nutritional composition comprises a mixture of galacto-oligosaccharides and fructo-oligosaccharides, more preferably transgalacto- oligosaccharides and fructo-oligosaccharides. Suitable non-digestible oligosaccharides are for example Vivinal®GOS (FrieslandCampina DOMO), Raftilin®HP or Raftilose® (Orafti). Preferably, the nutritional composition comprises 80 mg to 2 g non-digestible oligosaccharides per 100 ml, more preferably 150 mg to 1.5 g, even more preferably 300 mg to 1 g per 100 ml. Based on dry weight, the nutritional composition preferably comprises 0.25 wt% to 20 wt%, more preferably 0.5 wt% to 10 wt%, even more preferably 1 .5 wt% to 7.5 wt% of non-digestible oligosaccharides.

Formula

The use according to the present invention requires the administration of an infant formula, a follow- on formula or a young child formula. This means that the composition that is administered is not human milk. It also means that the composition that is administered is not native cow’s milk or native milk from another mammal. Alternatively, the terms as used herein, “infant formula” or “follow-on formula” or “young child formula” means that it concerns a composition that is artificially made or in other words that it is synthetic. Hence in one embodiment, the nutritional composition that is administered is an artificial infant formula or an artificial follow-on formula or an artificial young child formula or a synthetic infant formula or a synthetic follow-on formula or a synthetic young child formula.

In the present context, infant formula refers to nutritional compositions, artificially made, intended for infants of 0 to about 4 to 6 months of age and are intended as a substitute for human milk. Typically, infant formulae are suitable to be used as sole source of nutrition. Such infant formulae are also known as starter formula. Follow-on formula for infants starting with at 4 to 6 months of life to 12 months of life are intended to be supplementary feedings to infants that start weaning on other foods. Infant formulae and follow-on formulae are subject to strict regulations, for example for the EU regulations no. 609/2013 and no. 2016/127. In the present context, young child formula refers to nutritional compositions, artificially made, intended for infants of 12 months to 36 months, which are intended to be supplementary feedings to infants.

The nutritional composition for use according to the present invention comprises digestible carbohydrates, protein and lipid, wherein preferably the lipid provides 30 to 60 % of the total calories, the protein provides 5 to 20% of the total calories and the digestible carbohydrates provide 25 to 75% of the total calories.

The nutritional composition is preferably an infant formula or follow-on formula and preferably comprises 3 to 7 g lipid/100 kcal, preferably 4 to 6 g lipid/100 kcal, more preferably 4.5 to 5.5 g lipid/100 kcal, preferably comprises 1.7 to 3.5 g protein/100 kcal, more preferably 1.8 to 2.1 g protein/100 kcal, more preferably 1.8 to 2.0 g protein/100 kcal and preferably comprises 5 to 20 g digestible carbohydrate/100 kcal, preferably 6 to 16 g digestible carbohydrate/100 kcal, more preferably 10 to 15 g digestible carbohydrate/100 kcal. Preferably the nutritional composition is an infant formula or follow-on formula, and preferably has an energy density of 60 kcal to 75 kcal/100 ml, more preferably 60 to 70 kcal/100 ml, when in a ready-to-drinkform. This density ensures an optimal balance between hydration and caloric intake. In one embodiment, the nutritional composition is a powder. Suitably, the nutritional composition is in a powdered form, which can be reconstituted with water or other food grade aqueous liquid, to form a ready-to drink liquid, or is in a liquid concentrate form that should be diluted with water to a ready-to-drink liquid. The infant formula, follow-on formula or young child formula according to the invention have small lipid globules, hence with a mode diameter, based on volume, of about 0.3-0.5 pm.

In this document and in its claims, the verb "to comprise" and its conjugations is used in its nonlimiting 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 : Effect of lipid source on fat mass in offspring of dams with gestational diabetes

An experiment was performed wherein the effects of an infant milk formula (IMF) comprising predominantly vegetable fat as the lipid component (IMF 1 ; control) was compared with an experimental IMF comprising as the lipid component a mixture of vegetable fat and milk fat (IMF 2).

GDM mouse model

A gestational diabetes mellitus (GDM) mouse model was used to generate offspring which was exposed to GDM conditions during gestation. The dams received 2 triggers before pregnancy in order to induce a transient GDM condition. This approach reflected the GDM pathophysiology in a pilot study (Li et al. Journal of Endocrinology 2020, 244:501-510).

At 12 weeks of age C57BL/6N dams were fed with a 60 energy % high fat diet (HFD) for 4 weeks to reduce insulin sensitivity. The HFD was based on AIN93G diet with an adjusted lipid fraction containing 60 energy % lipid. A low dose of streptozotocin (60 mg STZ/kg) was administered to a subset of dams on 3 consecutive days prior to mating. STZ is an alkylating agent that selectively kills pancreatic beta-cells via cell necrosis and/or apoptosis. By administering low doses of STZ, the beta-cell capacity is reduced and a GDM phenotype develops during pregnancy. The offspring was breastfed/lactated with breast milk till PN16. At PN16, GDM dams and litters were given either control IMF 1 (n=11) or experimental IMF 2 (n=11). The male offspring were weaned at PN21 and continued on the same IMF diet (1 or 2) until PN42. The offspring was subsequently fed with Western-style diet (WSD) for 68 weeks. The WSD was based on AIN93G diet with an adjusted lipid fraction containing 45 energy% lipid.

At PN84, the male offspring were assessed for body weight (using standard scale) as well as fat mass and lean mass, using an MRI analyser (EchoMRI-100H, EchoMRI) per manufacturer’s instructions.

Diets

The offspring diets comprised a macronutrient and micronutrient composition following AIN93G. The offspring diets consisted of 28.3% (w/w) IMF 1 or IMF 2. Protein, carbohydrates, and micronutrients were added to match AIN93G. The fat components were derived entirely from the IMF. The fat content and fatty acid profile of the diets comprising IMF 1 and IMF 2 were similar (Table 1). For control IMF 1 a mixture of palm oil, coconut oil, low erucic acid rape seed oil, sunflower oil, high oleic sunflower oil, with a small amount of soy lecithin, and LC-PUFA premix was used. The amount of vegetable lipid in the final control IMF was about 98 wt% based on total fat, and the amount of mammalian milk fat about 1 wt%. For experimental IMF 2 a mix of anhydrous cow’s milk fat, coconut oil, low erucic acid rape seed oil, sunflower oil, high oleic acid sunflower oil, with a small amount of soy lecithin and LC-PUFA premix was used. The amount of vegetable lipid was about 51 wt% based on total fat, and the amount of mammalian milk fat about 48 wt%.

Table 1. Characteristics of the IMF powder

Further characteristics of the fat component of the different experimental IMFs used for the different IMFs are shown in Table 2.

Table 2

Results

At PN84 the body weight and adiposity were measured. Table 3 shows the body weight and lean body mass at PN84, as well as the fat mass, lean mass and percentage fat mass at PN84. The differences between the two groups were assessed using an independent samples t-test for each outcome measure. Table 3

* p-value < 0.05, significantly different from GDM + IMF 1 ** p-value < 0.01 , significantly different from GDM + IMF 1 As can be deduced from Table 3, whilst there was no difference in body weight at PN84, the levels of fat mass and percentage fat mass in mice from GDM mothers who consumed IMF 2 in early life was significantly reduced compared to the fat mass in the mice from GDM mothers that consumed IMF 1 in early life. This was in line with a concomitant significant increase in lean body mass in mice from GDM mothers exposed to IMF 2 in early life compared to mice from GDM mothers exposed to IMF 1 in early life. Decreased fat mass, percentage fat mass and increased lean mass after exposure to a WSD is considered healthier and is indicative of better metabolic handling of the dietary challenge and reduces the risk of becoming obese later in life.

Since the overall fatty acid composition in the diets was very similar, it is surprising that the difference in lipid component, thus the inclusion of milk fat rather than solely vegetable fats, in an IMF fed early in life has such a programming effect towards reduction in fat mass and investment in lean body mass during the WSD challenge

Example 2: Follow on formula Follow on formula, intended for infants over 6 months of age, comprising per 100 ml, after reconstituting 14.55 g powder to an end volume of 100 ml:

68 kcal,

1.36 g protein (whey protein/casein weight ratio 4/6),

8.1 g digestible carbohydrates (mainly being lactose), - 3.2 gram fat (of which about 50 wt% cow’s milk fat, the remainder being vegetable oils, fish oil and microbial oil).

0.8 g non-digestible oligosaccharides, 0.08 g long chain fructo-oligosaccharides (source RaftilineHP), 0.72 g galacto-oligosaccharides (source Vivinal GOS), minerals, vitamins, trace elements and other micronutrients as according to directives for infant formula.