Milk and the Prevention of Metabolic Disease

Dietary calcium plays a pivotal role in the regulation of blood pressure and energy metabolism/obesity risk.  Intracellular calcium ([Ca2+]i) is a fundamental factor linking these conditions, and modulation of [Ca2+]i in target tissues  by calcium-regulatory hormones provides an opportunity to modulate disease risk with dietary calcium.  The increase in calcitriol in response to suboptimal calcium diets increases vascular smooth muscle [Ca2+]i and thereby increases blood pressure, while suppression of calcitriol with dietary calcium normalizes [Ca2+]i and thereby reduces blood pressure. Further, dairy calcium sources are markedly more effective than supplementary sources in controlling blood pressure, as they contain complementary bioactive components, such as ACE inhibitors. [Ca2+]i is also a key regulator of adipocyte metabolism, as increased [Ca2+]i stimulates lipogenic gene expression and activity and inhibits lipolysis,  resulting in increased adipocyte lipid accumulation and net adiposity.  Further, calcitriol stimulates adipocyte Ca2+ influx and inhibits both uncoupling protein 2 (UCP2) expression and apoptosis, thereby promoting adiposity, while dietary calcium-suppression of calcitriol reduces adiposity.  In support of this concept, low calcium diets accelerate weight gain and fat accretion in obesity-prone transgenic mice, while high calcium diets markedly inhibit lipogenesis, accelerate lipolysis, and suppress fat accretion and weight gain in animals maintained at identical caloric intakes and markedly accelerate fat loss secondary to caloric restriction.  These concepts are confirmed by epidemiological and clinical trial data, both of which confirm protection from obesity with high calcium intakes.  As with hypertension, dairy sources of calcium exert a markedly greater “anti-obesity” effect.  This is likely attributable to additional bioactive compounds in dairy which act synergistically with calcium to attenuate adiposity; these include angiotensin converting enzyme (ACE) inhibitory peptides which limit angiotensin II stimulation of adipocyte lipogenesis and leucine, which stimulates skeletal muscle protein synthesis, thereby promoting a shift from energy storage in adipose tissue to utilization in muscle to support the energetic cost of protein synthesis.  Further, studies using calcium-depleted milk indicate that calcium is responsible for ~40% of the “anti-obesity effect of milk, with other components (including ACE inhibitors, leucine, and others) accounting for the remainder. 

Obesity results in increased oxidative stress.  Because calcitriol stimulates Ca2+ signaling and inhibits UCP2 expression, it may accelerate reactive oxygen species (ROS) production and/or inhibit ROS clearance.  Conversely, suppression of calcitriol with higher dairy diets may reduce ROS production. Our recent data support these concepts, with calcitriol reducing ROS scavenging and causing increased ROS levels in adipocytes, while increasing dairy intake reduces ROS levels in adipose tissue and skeletal muscle.  This regulation of ROS production may provide a link between dairy consumption and inflammation in obesity, and we have found calcitriol to promote expression and secretion of inflammatory adipokines and suppress anti-inflammatory adipokines, while dairy suppression of calcitriol suppresses inflammatory cytokines in vivo.  Thus, increasing milk and milk product intake not only reduces the risk of hypertension and obesity, but may independently reduce oxidative stress and inflammation.