Progressive weight gain year-on-year, sufficient to drive significant increases in the prevalence of overweight and obesity, is a well-recognised feature of the menopause transition, together with quantitatively smaller but similarly important losses of lean tissues, chiefly muscle and bone. However, the mechanisms that underlie these changes and the nature of the interactions between them have been unclear. Based on analysis of nutritional changes during the menopause transition we identify enhanced bodily protein breakdown as a putative trigger for weight gain via a mechanism known as the Protein Leverage Effect. It arises when progressive net bodily protein losses induce increased appetite for protein. If there is not a corresponding increase in the dietary protein concentration, the predicted consequence is excess non-protein energy intake. Based on data from published clinical research studies, we show how weight gain and adiposity, as well as lean tissue losses, might be ameliorated or even prevented by a small adjustment upwards of 1–3% (digestible energy; DE) in dietary protein concentration, from around 16–17% DE if there is no change in physical activity, or to 19% DE if there is an accompanying reduction in physical activity of around 10%. In both cases the analysis predicts that an increase in dietary protein concentration can be achieved by making relatively small adjustments to the composition of the ‘standard daily menu’. The concept is provided in schematic form in Figure 1. Menopause arises from an age-dependent loss of ovarian follicles and, in turn, a progressive failure of the endocrine mechanisms that support female fertility, dependent in part on the cyclical production of pituitary FSH and ovarian estrogens (see review1). Along with the loss of menstrual periods, the menopause transition is marked by phenotypic changes including body weight gain associated with increased fat mass and decreased lean body mass associated with reduced skeletal muscle mass and net bone resorption.2-4 The increase in body weight is sufficient to drive an age-related increase in the prevalence of overweight and obesity.5 In consequence, there are enhanced risks of cardiometabolic diseases, sarcopenia and osteoporosis.4, 6, 7 Potentially important increases in regional adiposity have also been described in the menopause transition, including increased central adiposity8 and increased cardiovascular fat depots, which contribute to the risk of coronary heart disease.9 These medically important manifestations of the menopause, increased fat mass and reduced muscle and bone masses, can be explained if the primary hormonal changes described above produce, first, net protein breakdown and, second, increased dietary intake not only of protein but also of non-protein energy to drive accumulation of fat stores. Two interacting mechanisms drive net protein breakdown in menopausal women: (i) enhanced protein breakdown, which is acutely reversible with estrogen replacement10 and (ii) impaired protein synthesis, arising from anabolic resistance to dietary protein, which occurs in men as well as women and is associated with advancing age,11, 12 and in the context of delayed healing following certain muscle injuries (see review13). Protein breakdown in the menopause transition arises, in part, from local increases in pro-inflammatory cytokines, tumour necrosis factor (TNF)-alpha and interleukin-6.14-16 Impaired protein synthesis, on the other hand, has been linked to impaired function of key mTOR pathways and is potentially amenable to strategies that promote the production of growth factors and/or stimulate growth factor receptor signalling pathways.17 Only the former mechanism (i.e. enhanced protein breakdown in the context of estrogen withdrawal) would appear to be relevant to the present discussion relating to protein losses and an enhanced drive for protein intake and, in turn, energy intake during the menopause transition. Recent work has identified Fibroblast Growth Factor 21 (FGF21), a 181-amino acid peptide synthesised primarily in the liver18 but also in muscle,19 as a hormonal signal of protein deficiency, which can be triggered by low protein intakes in both mice and humans.20-23 One key effect of FGF21 whether delivered into the blood or the cerebrospinal fluid is to stimulate feeding and either promote a preference for foods that are high in protein concentration (%P) or induce increased consumption of a diet of a fixed %P.24 Larson et al. described similar results, in which male mice injected intraperitoneally with FGF21 respectively increased and decreased their intakes of protein-rich and carbohydrate-rich foods25 (see review26). In both these studies, no change in total energy intake was observed when a choice of foods of different macronutrient compositions enabled increased protein intake without commensurately increasing energy intake. These findings are consistent with dietary studies demonstrating the existence of a protein-specific appetite27-30 and raise the possibility that the appetite response to enhanced protein breakdown in lean tissues and/or to reduced protein stores is also mediated by the prevailing plasma level of FGF21. A specific appetite for protein dominates regulation of energy intake in many animals, humans included, when faced with nutritionally imbalanced diets—a phenomenon termed protein leverage.31 Hence, when protein becomes diluted in the food supply by fats and carbohydrates, more energy is necessarily ingested in attaining the target intake of protein that signals satiety. Conversely, as protein becomes more concentrated in the diet, total energy intake is restricted.32 Dilution of protein in the food supply has occurred progressively since World War 2, driven by the development and availability of mass-produced, hyper-palatable, energy-dense, processed foods and beverages.33, 34 Such foods not only dilute protein in the food supply—their sensory characteristics (notably highly palatable combinations of sweet, fat, salt and umami flavours) also misdirect individuals' macronutrient selection towards lower-protein foods.35 Overconsumption of energy also arises from protein leverage if the requirement (‘regulatory intake target’) for protein increases but dietary protein density is unchanged relative to fat and carbohydrate. Protein requirements increase at times of anabolic demand (e.g. for growth and reproduction) or enhanced net protein breakdown, as described above for the menopause transition. In these circumstances, achieving a higher protein target without exceeding energy needs requires a change in macronutrient balance towards a higher percent protein diet.31, 32 During the menopause transition, enhanced protein breakdown from lean tissues arising from estrogen loss and/or FSH excess, regardless of whether there are immediate lean tissue losses, is predicted to shift the regulatory targets for protein and energy, increasing the general target level for protein and, in some individuals, reducing energy needs. Unless the composition of the habitual diet changes towards a higher percent protein and exercise is maintained or increased, protein leverage drives excess energy intake, promoting overweight and its cardiometabolic consequences. The situation is exacerbated in individuals in whom there is reduced physical activity, which is positively associated with lean mass in menopausal women.36 To explore the effects, we have developed a graphical model in two steps in Figure 2, based on nutritional geometry and values derived from the published literature. In Figure 2A, we consider an uncomplicated increase in protein requirements arising from net protein breakdown in muscle and bone. The black bullseye indicates hypothetical daily target intakes for protein and non-protein energy prior to menopause. This combination (85 g protein and an energy intake of 2122 kcal (8.9 MJ), of which 1782 kcal (7.5 MJ) is in the form of non-protein energy, i.e. carbohydrates and fats), represents a 16% DE protein diet (the black radial). The red bullseye provides an estimate of the shift required during the menopausal transition to a higher protein (91 g) target at the same total energy requirement of 2122 kcal (8.9 MJ). Attaining this new target requires a dietary shift to 17% DE protein (the red radial). However, were the individual to remain on a 16% DE protein diet, achieving her elevated protein intake requirement of 91 g per day would bring additional energy, an extra 153 kcal (0.64 MJ) per day (purple arrow). In Figure 2B, we consider a situation in which the increased protein target of 91 g is accompanied by a reduced energy target from 2122 to 1925 kcal (8.1 MJ) arising from a 9–10% reduction in physical activity. Achieving the increased protein target in this case requires a dietary shift to 19% DE protein; i.e. an increase of almost 20% above baseline. For an individual consuming protein at 1.0 g kg−1 day−1 this represents an increase to around 1.2 g kg−1 day−1. Were she to remain on a 16% DE protein diet, this would require an extra 360 kcal (1.5 mMJ) per day. Failure to increase energy intake on the existing 16% DE protein diet would lead to deficient protein intake, exacerbating lean mass loss, whereas consuming the extra 360 kcal would protect lean mass by achieving the increased protein target but risk weight gain, especially if accompanied by a reduction in physical activity (4). A combination in which the upwardly revised protein target is not achieved and there is ingestion of excess energy, risks both lean mass loss and weight gain. When an aerobic exercise programme was prescribed for premenopausal women (ages 19–45) in combination with a reduced energy, high- (30% DE) or standard- (15% DE) protein diet, fat mass decreased more markedly and lean mass increased in the high-protein group.51 In addition, protein supplementation augmented the positive effect of resistance training on skeletal muscle mass and performance in a meta-analysis of 22 studies that included premenopausal and postmenopausal women.52 The main points are presented in Box 1. Based on the current state of knowledge, the following points seem reasonable. Women entering the menopause transition (around age 40–45) should be assessed for body weight, body mass index (BMI), cardiovascular health, lean body mass, skeletal health and musculoskeletal fitness. Diet and its composition should be assessed for total energy intake and protein concentration. Aerobic and resistance exercise schedules as well as general physical activity should be reviewed and new programmes developed as appropriate. Options for increasing dietary protein concentration should be provided and progress monitored. Dietary protein concentration should increase from a minimum of 16% DE (around 1.0 g kg−1) at age 40, to 18–20% DE (around 1.2 g kg−1) at age 50, and total energy intake should be reduced by around 10%, to ~8 MJ day−1. Removing ~250 kcal (1.0 MJ) per day of processed fats and carbohydrates lowers energy intake and increases percent protein and could help to solve the problem long-term. A detailed discussion of these issues is beyond the scope of the present analysis. Population level data for the menopause transition demonstrate there are significant lean tissue losses along with more substantial increases in fat mass.3 This finding suggests that additional food intake, sufficient to drive enhanced adiposity and weight gain, is insufficient to overcome protein losses in muscle and bone in many women. In consequence, there are enhanced risks of sarcopenia and osteoporosis, as well as overweight and obesity, particularly with advancing age. Protein losses may arise if increased protein intake is insufficient to offset increased losses, as would be the case if the operation of the Protein Leverage Effect were incomplete (i.e. increased energy intake without fully satisfying the enhanced protein requirement).32 In addition, partial anabolic resistance to dietary protein may impair muscle synthesis11 and perhaps also bone protein synthesis in some women, even at relatively early stages of the menopause transition. Thus, increases in dietary protein concentration in the range revealed by our analysis (around 1–3% DE) may not only address the problem of increased energy intake but also, at least partially, overcome anabolic resistance and restore lean tissue masses. As anabolic resistance worsens with advancing age, further increases in protein intake may be required.53-56 These matters were discussed in a 1-hour session with six members of a women's consumer advisory group linked to the Community Menopause Service at Concord Hospital Sydney. Several of these women had sought advice on managing medical or health issues related to the menopause. There was immediate recognition of the problem: that a significant proportion of women undergoing the menopause transition report weight gain of 1–2 kg per year despite no changes in the foods they are eating or in the level of physical activity. However, the concern was expressed that many women would be unable to identify clearly low or high protein foods, suggesting the need for targeted education. This advice is consistent with the outcomes of a recent large study on ‘Protein Knowledge’ among older women and men.57 Given the precise nature of the quantitative changes required in protein intake, this warrants particular attention. The proposed intervention is a dietary modification alone that increases %P by 3% DE from the individual's baseline level, which is expected to increase total protein intake by 0.1–0.2 g kg−1 day−1, and lower total energy intake by 5–10%, i.e. by 6–12 kJ kg−1 day−1. The primary outcome measure will be body weight change with secondary outcome measures of fat and lean tissue masses by whole body DXA. The study will include women aged 40–50 years who have entered the menopause transition (variable duration of menstrual bleeding and/or intervals of amenorrhea ≥60 days) but are not yet postmenopausal (at least one menstrual period in the previous 12 months) with a BMI 18.5–29.5 kg m−2 and a habitual protein intake of 12–16% DE. Women meeting the inclusion criteria will be randomised to either (i) their normal diet with advice provided on healthy food options (control group) or (ii) the modified diet as described above (test group). The baseline level of physical activity will be determined by pedometry and monitored at 6-monthly intervals over the course of the study. Study participants will be encouraged to maintain physical activity at current levels provided they are completing a minimum number of steps as informed by published studies.58 Based on the expected size of the effect (0.5 kg body weight gain per year in controls; 0.5 kg body weight loss per year in subjects on the modified diet) we propose a 4-year study with group sizes of 460 women in the control group and 460 women in the diet modification group (alpha 0.05, power 90%, drop-out rate 20%). The number of participants required would fall if change in adiposity rather than change in body weight3 is selected as the primary outcome measure. The study will also include 6-monthly reviews of dietary intake, with renewed advice, as well as body weight determination and physical activity monitoring, together with annual measurements of whole body composition by DXA for adipose and lean tissue masses. Prof. Stephen Simpson is Academic Director of the Charles Perkins Centre at the University of Sydney. He was responsible for the primary concept, established the overall plan for the write-up, including key elements of the background literature search and discussion, undertook the modelling by nutritional geometry, and initiated the write-up and was essential to its completion. Prof. David Raubenheimer is the Leonard P. Ullman Chair in Nutritional Ecology and leader of the Nutrition Theme at the Charles Perkins Centre. Prof. Raubenheimer co-developed the primary concept, checked the results of the modelling by nutritional geometry, and contributed to all stages of the write-up, including editing and proof-reading. Prof. Kirsten Black is an academic gynaecologist at the University of Sydney, who leads the Menopause service at Concord Repatriation General Hospital. Prof. Black contributed to the development of the Protein Leverage concept for menopausal women, led the discussion of the findings and translational opportunities with a consumer group of menopausal women, and assisted with the write-up, editing and proof-reading. Prof. Em Arthur Conigrave is a Molecular and Clinical Endocrinologist based at the University of Sydney and Royal Prince Alfred Hospital. He developed the primary concept in the context of the major endocrine and metabolic changes of the menopause transition, established the proposed pathophysiological sequence of events, drafted several sections of the manuscript and took overall responsibility for editing, proof-reading and article submission. The authors would like to thank Sarah Carter (PhD student), who assisted with scheduling and facilitating the discussion with members of a women's consumer advisory group. Open access publishing facilitated by The University of Sydney, as part of the Wiley – The University of Sydney agreement via the Council of Australian University Librarians. None declared. Completed disclosure of interest forms are available to view online as supporting information. No human or animal approvals were required. Data sharing not applicable - no new data generated. ICMJE ICMJE ICMJE ICMJE Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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