The prevalence of obesity and associated co-morbidities such as diabetes are increasing world-wide, arising due to calorie intake exceeding their use inside the body. The excess calories (energy) then get stored as fat inside the body in specific tissues called adipose. If this persists, the adipose tissues expand to the point that any extra dietary fat (coming in the diet) spills-over into other tissues. This causes inflammation and loss of tissue functions, leading to the development of clinical conditions. There are many reasons why we cannot match intake of calories to the demand in the body. The main reasons are, our genes, the micro-organisms living in the gut and environmental factors such as the diet. These interact and influence weight gain. We obviously cannot change our genes, but we can change our diet, and in doing so, influence the interaction between the micro-organisms (or microbes/microbiota) and the genes. Thus, our aim is to develop dietary interventions that can prevent weight gain or cause weight loss by modifying the microbe/gene interaction linked to accumulation of excess calories inside the body (which is called a positive energy balance). To this end, we have been assessing how bovine milk associated whey proteins affect the balance between what we eat and what is stored in the body as fat, with the view to developing these nutrients as anti-obesity dietary interventions. Why? Because (1) milk has been part of our daily diet for millennia because it is an important source of nutrition, with an undiscovered potential to also improve health, (2) whey proteins, which include bovine serum albumin (BSA), lactoferrin (Lf) and alpha lactalbumin (LAB), can be separated from casein (another milk associated protein) during cheese manufacture and thus, the Irish dairy industry has a significant interest in channelling such by-products back into human consumption as functional food ingredients for improving human health; and (3) whey proteins are a rich source of branch chain amino acids, such as leucine, which are found in high abundance compared to casein or many other plant proteins, and this difference in amino acid composition is thought to underline how whey proteins improve body composition (fat to lean mass). A great deal of work has been done to determine the impact of whey proteins on body weight. Notably, Hall et al., 2003 (British Journal of Nutrition; 89; 239-248) showed that whey proteins cause satiety acutely in humans and this can be associated with an increased production of related hormones such as CCK and GLP-1. Subsequent work conducted in rats showed that the chronic intake of whey proteins reduces body weight without relying on changes in food intake (Zhou et al., 2011; Obesity; 19; 1568-1573). This work suggested that there are other mechanisms through which dietary whey proteins reduce body weight gain. The latter observation prompted us to look for the underlying mechanism for a food-intake independent effect on body weight. Since starting this work in Teagasc Food Research Centre, Fermoy, Ireland, in 2011/2012 period, we have published a series of articles looking at the long term effects of whey protein intake in humans and animals. This work focused on both the protein enriched form of whey, known as whey protein isolate (WPI) and the associated individual whey proteins such as BSA, Lf and LAB. From this work, we established that (1) WPI alters the gut microbiota, (2) this modifies the host nutrient supply in the gut, (3) the gut size reduces as well as its permeability (leakiness), which together alters nutrient passage into the body, (4) in parallel, some internal tissues reduce in size, while others do not respond, (5) there is targeting mechanism employed by whey proteins to select which tissues to alter in size. For the adipose tissue, this mechanism can be used to reduce either the visceral adipose tissue or the subcutaneous adipose tissue, where the selectivity of the tissue is based on the interaction between whey proteins and other macronutrients in the diet, namely dietary fat and carbohydrates. This interaction affects the gut microbiota and hence the host nutrient supply in the gut. Importantly, this impact can be exploited to potentially alter the male and female body shape, since males store dietary fat mostly in the visceral around the abdomen area, while females store dietary fat mainly in the subcutaneous around leg and thigh areas. (6) seeing these changes in the tissues, compensatory mechanisms start to act to increase intestinal size and atttempt to improve nutrient absorption through the intestine. New hypothesis: Based on 1-5, we hypothesised that long term intake of whey proteins alter the host nutrient supply in the intestine via changes in the microbiota. The modified nutrients shrink the gut by affecting genes. Additionally, the modified nutrients also target specific internal tissues (such as the adipose) and affect their genes, causing the tissues to also shrink, while other tissues that are not targeted remain unresponsive. The impact on the adipose tissues can be tailored to affect tissues located in the visceral or subcutaneous compartments. These effects are independent of intake. To minimize the above effects, and to protect the adipose tissues from shrinkage, we propose that there are active mechanisms trying to absorb more nutrients through the intestine (point 6), and prevent the shrinkage of the adipose tissues. Protecting the adipose tissue in this way is important because the adipose tissues act as a reservoir of stored fat and releases these to the rest of the body if there is a shortage in the external supply (e.g. food shortage). Importantly, the effects of whey proteins on 1-5, seemed to override the effects of 6, leading to reduced weight gain. **Work on mechanisms 1-5:** With funding from Teagasc, SFI-BBSRC partnership and VistaMilk Research Centre, we have elucidated part of the mechanism related to points 1-5 (see Nychyk et al., 2021). With further funding from SFI-DAFM-ERDF, and as part of the VistaMilk Research Centre, we have elucidated part of the whey sensitive gut microbiota-mechanism that targets the visceral adipose tissue or the subcutaneous adipose tissue. The uniques of this mechanism was highlighted by showing that neither calorie restriction nor bariatric surgery has the selectivity to affect one type of tissue, as both these interventions reduce both tissues (see Nilaweera and Cotter, 2023). **Work on mechanism 6** The existence of the above mechanism led us to look for compensatory mechanisms that promote gut growth, specifically with links to the shrinkage of the adipose tissue. To this end, we looked at scenarios that also cause fat loss in a wide variety of species, namely mammals, reptiles and birds. These scenarios are bariatric surgery, calorie restriction, cold exposure and lactation. In all of these cases, we noted that the reduction in adipose tissues also cause the growth of the intestine and that these changes were accompanied by altered brain (hypothalamic) expression of genes. Interestingly, further review of the data revealed that signals generated during adipose loss that affect hypothalamic genes, extend and cause the growth of the intestine. This body of work has been published by us (Nilaweera and Speakman) in 2018 in the Obesity Reviews. Collaborators linked to this research program are Prof. John R. Speakman (University of Aberdeen/Chinese Academy of Sciences, Beijing, China) Prof. Paul Cotter (Teagasc) Prof. John F. Cryan (UCC) Prof. Lorraine Brennan (UCD) Dr. Jun Wang (CAS, China) Prof. Donagh Berry (Teagasc).