Obesity and cardiometabolic risk, or the metabolic syndrome, continue to be major public health concerns. To date, treatment with lifestyle and pharmacotherapy interventions has resulted in limited efficacy in reversing the upward trend in this present-day health crisis. Research reveals that a modest 5% to 10% weight loss results in substantial improvement in health. While obtaining modest weight loss is often achievable, maintaining lost weight is challenging. Research has recently improved our understanding of several endogenous pathways that influence body weight regulation and disease risk.