3
Complications of Obesity
Adiposopathy (Sick Fat Disease)
➤ Adipocyte hypertrophy: Abnormal enlargement of adipocyte cells
due to excessive lipid accumulation.
➤ Chronic low-grade inflammation: As adipocytes enlarge, they
become metabolically dysfunctional, secreting proinflammatory
cytokines such as tumor necrosis factor α (TNF-α) and interleukin
6 (IL-6), and decreasing the production of anti-inflammatory
adipokines such as adiponectin. Increased release of free fatty
acids (FFAs) also rise, contributing to systemic inflammation and
macrophage activation within adipose tissue.
➤ Immune dysregulation: In response to these inflammatory and
metabolic disturbances, macrophages in adipose tissue shift
toward a proinflammatory (M1-like) phenotype. These activated
macrophages disrupt insulin signaling in adipocytes and other
tissues, promoting FFA accumulation and insulin resistance.
Ongoing crosstalk between adipocytes and macrophages
perpetuates this inflammatory cycle.
➤ Endocrine dysregulation: Adipose tissue dysfunction leads to insulin
resistance which can result in hyperinsulinemia and hyperglycemia. The
proinflammatory cytokines mentioned above, together with adipokines
such as leptin and FFAs, disrupt the hypothalamic-pituitary-ovarian
(HPO) axis. For example, pulsatile gonadotropin-releasing hormone
secretion is impaired, leading to abnormal sex hormone levels.
➤ Disrupted neurohormonal signaling: Leptin resistance in obesity
may lead to elevated leptin levels, which can activate the sympathetic
nervous system (SNS) and the renin-angiotensin-aldosterone
system (RAAS). Satiety signaling is impaired due to central insulin
resistance and leptin resistance. Lastly, increased circulating
FFAs and chemokines upregulate pain signaling, leading to pain
hypersensitivity.
➤ Tissue hypoxia and fibrosis: Adipocyte expansion can outpace
angiogenesis, leading to tissue hypoxia. Profibrotic genes are
upregulated, resulting in extracellular matrix deposition and collagen
cross-linking, which worsen tissue hypoxia and promote fibrosis.
Connective tissues in other organs are altered (e.g., cartilage in
joints), leading to inadequate resistance to compressive forces.
Biomechanical Forces (Fat Mass Disease)
➤ Increased adipose tissue deposition creates compressive forces,
leading to premature mechanical wear in joints. Increased joint
loading alters gait and muscle activation patterns, potentially leading
to fatigue and disrupted muscle mechanics. Intraabdominal pressure
increases venous pressure, leading to stasis and edema. Deposition of
adipose tissue can lead to noncompressive paracrine effects, such as
epicardial fat-mediated inflammation affecting cardiac function.
