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To conduct a systematic literature review to determine if physical activity is associated with prevention of weight gain in adults.The primary literature search was conducted for the 2018 Physical Activity Guidelines Advisory Committee and encompassed literature through June 2017, with an additional literature search conducted to include literature published through March 2018 for inclusion in this systematic review.The literature review identified 40 articles pertinent to the research question. There is strong evidence of an association between physical activity and prevention of weight gain in adults, with the majority of the evidence from prospective cohort studies. Based on limited evidence in adults, however, there is a dose–response relationship and the prevention of weight gain is most pronounced when moderate-to-vigorous intensity physical activity (≥3 METs) is above 150 min·wk−1. Although there is strong evidence to demonstrate that the relationship between greater time spent in physical activity and attenuated weight gain in adults is observed with moderate-to-vigorous intensity physical activity, there is insufficient evidence available to determine if there is an association between light-intensity activity (<3 METs) and attenuated weight gain in adults.The scientific evidence supports that physical activity can be an effective lifestyle behavior to prevent or minimize weight gain in adults. Therefore, public health initiatives to prevent weight gain, overweight, and obesity should include physical activity as an important lifestyle behavior.