1a. Objectives (from AD-416):
To determine how nutritional, hormonal, and physiological factors affect bone loss/gain in obesity through modifying obesity-induced inflammatory stress. Specifically, we will determine the extent to which obesity is associated with elevated levels of pro-inflammatory cytokines known to promote bone resorption, determine how obesity affects functions of bone cells and bone metabolism, determine the extent to which existing chronic inflammatory stress (induced experimentally by lipopolysaccharide implantation), estrogen deficiency (affected by ovariectomy), and subclinical magnesium intake impair bone health in obese animal models and in obese human subjects, and determine how moderate physical activity preserves bone structure as compared to caloric restriction during weight reduction in an obese animal model.
1b. Approach (from AD-416):
Studies will utilize cell culture, animal models and human subjects. We will use diet-induced obese mice or rats to determine the mechanisms by which adiposity interacts with other dietary, hormonal and physiological factors, such as estrogen deficiency, chronic inflammation, magnesium intake, and moderate exercise, and affects bone structure and functions of osteoblasts and osteoclasts. Human studies will use the in-house Community Studies Unit and the Metabolic Research Unit to conduct supplementation and controlled feeding experiments, respectively. We will determine whether 300 mg/d Mg supplementation to obese postmenopausal women with suspected marginal magnesium deficiency, ameliorates pro-inflammatory cytokine production and improves biomarkers of bone resorption and formation balance.
3. Progress Report:
An animal study was conducted to determine whether obesity exacerbates the bone loss induced by chronic inflammation. Forty-eight female C57BL/6J mice aged 6-wk-old were randomly assigned to four groups in a 2 x 2 factorial design: control or 1.5 µg/d lipopolysaccharide (LPS) and fed either normal-fat control diet or a high-fat diet. LPS was used to stimulate an inflammatory response. Animals were implanted a slow release LPS or a placebo pellet subcutaneously in the dorsal region of the neck. Data have been collected and are prepared for publication. A human study was completed to determine optimal protein intake and musculoskeletal response to energy deficit. Thirty-nine physically active volunteers aged 18 – 42 were recruited to participate in a 31-d live-in, controlled feeding study. Subjects were randomly assigned to three dietary groups: high protein (2.4 g/kg/d), moderate protein (1.6 g/kg/d), or low protein (0.8 g/kg/d). Using stable isotope methodology, muscle biopsies, and various molecular techniques, direct measures of muscle protein synthesis, protein breakdown, and the cellular mechanisms that regulate these processes were assessed following energy sufficient and insufficient diets. Markers of bone turnover and calcium homeostasis were also assessed. Data are currently being analyzed and summarized for publication. An experiment was completed to determine whether magnesium deficiency enhances or magnesium supplementation alleviates chronic inflammation and bone loss in obese and estrogen-deficient female rats. Female rats aged 65-75 days were assigned to dietary treatments of 50%, 100%, and 150% of the magnesium requirement and increased fat was supplied by high-oleic acid sunflower oil. Data are currently being analyzed and summarized for publication.
1. Alpha-1 antitrypsin reduces ovariectomy-induced bone loss. Increased production of cytokines causes inflammation and induces bone loss in postmenopausal women. ARS scientists at Grand Forks, ND investigated whether an anti-inflammatory agent, alpha-1 antitrypsin, protects estrogen deficient mice (a postmenopausal model) from bone loss. Estrogen deficiency resulted in significant bone loss, but mice treated with alpha-1 antitrypsin injection had increased bone mass and thickness compared to mice not treated with alpha-1-antitrypsin. These animal results provide insights for potentially using anti-inflammation agents as a tool to reduce bone loss in postmenopausal women.
2. High-protein diet preserves skeletal muscle mass and has no harmful effect on calcium balance during sustained energy shortage. Energy deficiency induces weight loss which may have negative effects on the muscle-bone system. Dietary protein intake in excess of the current national dietary recommendation may offer protection against these negative effects. ARS scientists at Grand Forks, ND, conducted a 31-d live-in, controlled feeding study to measure dietary calcium absorption, muscle protein synthesis, protein breakdown, and cellular mechanisms that regulate these processes. The data demonstrated that consumption of a high protein diet conserved muscle mass and promoted the loss of fat during sustained energy deficit. High protein diets have no negative effect on Ca absorption and Ca excretion. The results from this human study provide evidence useful for developing dietary strategies for protein intake to maintain healthy muscle and bones during energy deficit and weight loss.
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