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Learning Objective 1: The learner will be able to distinguish four pathophysiologic pathways leading to positive energy balance and excess weight gain.
Learning Objective 2: The learner will specify obesity assessment, prevention, and management strategies targeting the underlying the pathways to adipogenesis to advance clinical practice and research.
Methods: Theory synthesis was utilized to organize research findings of adipogenic factors into a taxonomy of obesity pathophysiology. A literature review based on search terms “obesity etiology,” “obesity pathophysiology,” and “adipogenesis” was conducted to identify defects in energy homeostasis associated with excess fat accumulation.
Results: Four pathways were identified by which energy homeostasis can be involuntarily disrupted through genetic and epigenetic influences. Adipose cell dysfunction includes excess adipose cell proliferation due to activation of gene transcription factors (thiazolidinediones, adenovirus-36, fatty acids), impaired fatty acid thermogenesis due to beta-adrenergic receptor polymorphisms, and decreased brown fat mass. Neuroendocrine hunger and satiety pathways can be disrupted due to factors including hyperinsulinemia, melanocortin receptor polymorphisms and anti-melanocortin receptor autoantibodies, sleep deprivation, and common medications. Impaired mitochondrial conversion of food substrates into cellular energy may involve impaired beta-oxidation of fatty acids, disruption of the tricarboxcylic acid cycle by medications and environmental exposures (beta adrenergic blockers, atrazine, dioxin, persistent organic pollutants). Chronic inflammation (gastrointestinal flora, high fat diet) has been shown to promote adipogenesis through lipopolysaccharide activation of nuclear factor kappa-B (NF-kB) and toll-like receptors in macrophages and adipocytes.
Conclusion: The Pathways to Obesity Model was constructed to show the inter-relationships between these patterns of obesity pathophysiology. The model provides a new taxonomy for a multi-pronged approach to assessing obese patients and new avenues for investigating targeted interventions to prevent and manage the disease.
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