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Physical activity (PA) positively influences health-related quality of life (HRQL), whereas obesity is associated with significant HRQL impairments. Active–obese persons often have similar or lower risk of cardiovascular outcomes and mortality than inactive–healthy weight persons; however, the combined PA–weight status effects on HRQL are unclear. The aim was to investigate the combined association of PA and body mass index (BMI) with HRQL in Canadian adults and older adults.Cross-sectional data included 110,986 participants ≥18 yr from the 2005 Canadian Community Health Survey, representing an estimated 22,563,527 Canadians. HRQL indicators included: Self-Rated Health (SRH), Participation and Activity Limitation due to illness/injury (PAL), and Total Disability Days (physical + mental) during the past 14 d (TDD). Prevalence of adverse HRQL was estimated by BMI, PA, and combined BMI–PA categories. Adjusted logistic regression was used to assess the odds of adverse HRQL by BMI, PA, and BMI–PA. Analyses were stratified by sex and age (18–44, 45–64, ≥65 yr).In both men and women of all ages, inactive individuals had greater likelihood of fair/poor SRH, and sometimes/often PAL, at all BMI levels; conversely, in active individuals, being underweight, overweight, or obese had little effect on SRH and PAL. Associations were weaker for TDD, where the greatest influence was in older adults from inactivity combined with underweight. Overweight showed less association to HRQL in males and older adults, whereas underweight showed stronger association in males and older adults.When examining BMI–PA in combination, PA emerges as the more important correlate of HRQL, regardless of weight status. This reinforces the importance of PA to health outcomes over and above the benefits related to weight loss or maintenance.