Introduction:Given the burgeoning prevalence of obesity and type 2 diabetes mellitus (T2DM), predicted to increase a further ~7.7% by 2030 (Chen et al. 2011), efforts to reverse or prevent the development of T2DM are critical. One way to navigate weight-management is through the use of a very low-calorie diet (VLCD), with the primary aims of achieving weight loss and improving insulin sensitivity (Weinheimer et al. 2010). While the causes of T2DM and obesity are multi-factorial, an area of current interest is the long-standing association between elevated circulating plasma branched chain amino acids (BCAA) and insulin resistance in T2D and obesity(Newgard et al. 2009). However, whether this relationship is causal remains to be determined. Here, we investigated the effects of 6-weeks VLCD upon circulating BCAA, in overweight, non-diabetic individuals, in order to explore any associations with weight loss and improvements in markers of metabolic health.Methods:Overnight fasted blood samples were taken from overweight (n=10, BMI 32±4 kg/m2), middle-aged men (~46±8y) before and after a 6-week period of nutritional intervention, employing VLCD meal replacement diets (Lighter Life). The VLCD programme consisted of 4 meals/day, providing ~600kcal/day (subjects were allowed upto 200kcal/day extra, in the form of fruit, vegetables or meat); providing a total of 50 g of protein, 50 g carbohydrate and ~17.3 g fat, complete with 100% RDA of vitamins and minerals. Body composition (lean body mass via DXA), was measured at the start and after 6 weeks, and blood analytes such as insulin (ELISA) and glucose (YSI) for calculation of insulin sensitivity were collected throughout. Plasma BCAA were determined by gas-chromatography mass spectrometry. Data were analysed by t-tests and Pearson’s correlation. Results:Six weeks of VLCD reduced body-weight (-11±3kg, P<0.0001), BMI (-3.4±0.8 kg/m2,P<0.0001) and improved HOMA-IR (P<0.05), while concomitantly reducing fat free mass (mainly muscle) (P<0.05). However, despite exhibiting elevated BCAA pre-VLCD (i.e. sum BCAA vs. age-matched controls, P<0.018), circulatory BCAA were unaffected by 6-weeks VLCD. There were no correlations with HOMA-IR, FFM or lean body mass and BCAA at baseline, or following VLCD. Conclusion:VLCD was effective for rapid induction of body weight loss, fat mass loss and reducing BMI, albeit with the unwanted side-effect of lean tissue loss (e.g. due to protein deficiency, release of glucogenic/ketogenic AA). Given the role of muscle in glucose disposal, future studies should seek VLCD-adjuvant atrophy mitigating strategies. Finally, the lack of reduction of circulatory BCAA despite improved insulin sensitivity following VLCD, challenges the notion BCAA are a causal driver of insulin resistance and thus a target of therapeutic value.