Disorders

Jimenez-Flores E et al. 2026. Review: adipose expandability failure, not fat mass per se, drives metabolic disease; bariatric surgery data confirm that restoring healthy expansion (hyperplasia over hypertrophy) reverses metabolic dysfunction.

Ruga S et al. 2026. Review of ferroptosis (iron-dependent lipid peroxidation cell death) in adipocytes: GSH depletion, GPX4 loss, and ACSL4-driven polyunsaturated lipid peroxidation drive the transition from hypertrophy to death; nutraceuticals (curcumin, resveratrol) modulate the pathway.

Defective subcutaneous adipogenesis produces insulin resistance independently of excess adipose mass, expanding the adipocyte dysfunction framework beyond obesity to lean insulin-resistant individuals.

Systematic review of 113 human and 29 animal studies: adipocyte hypertrophy is consistently associated with insulin resistance independent of total adiposity; weight loss reduces cell size and improves insulin sensitivity in parallel.

Weisberg et al. 2003. Up to 40% of obese adipose cells are macrophages. They account for nearly all TNF-alpha in fat; their number tracks adipocyte size and BMI.

Xu et al. 2003. Macrophage-specific and inflammation genes are upregulated in obese white adipose tissue in mice and humans, proposed as a direct cause of insulin resistance.

Virtue and Vidal-Puig 2010. A unified model: metabolic disease begins when adipose tissue exceeds its individual storage capacity, not simply when fat mass is high.

Weyer et al. 2000. Adipocyte hypertrophy, not adiposity alone, predicts insulin resistance; smaller cells are metabolically safer regardless of depot mass.

2025. NLRP3-Caspase-1 activation within CLS produces IL-1beta and worsens local and systemic insulin resistance; bariatric surgery reduces NLRP3 activity.

Depot-specific functional specialization means the same kilogram of fat in a visceral versus subcutaneous location carries a different disease risk.

Aberrant adipokine secretion and impaired adipose expandability are primary drivers of T2D; mechanism traced from hypertrophied adipocyte through portal FFA to hepatic insulin resistance. [URL corrected: previous link was a duplicate of the adipokine editorial]

snRNA-seq of FPLD2 adipose reveals suppressed lipid and mitochondrial gene programs alongside elevated inflammation; the adipocyte is failing before it disappears.

2025 synthesis of how adipose dysfunction from obesity to lipodystrophy impairs systemic metabolic homeostasis: the same depot failing in opposite directions.

Nnyamah C et al. 2026. Free Fatty Acid Receptor 2 (FFA2/FFAR2) on adipocytes suppresses adipose tissue inflammation; mice lacking adipocyte FFA2 show worsened inflammatory phenotype and disrupted intestinal lipid absorption.

2025 review highlighting the clinical and molecular heterogeneity of lipodystrophy; the shared phenotype of fat loss conceals fundamentally different mechanisms requiring different management.

Garg 2004. Congenital and acquired lipodystrophies: loss of adipose tissue leading to leptin deficiency, hypertriglyceridemia, and insulin resistance. Proves that too little fat is as dangerous as too much.

Montague et al. 1997. First human case of congenital leptin deficiency, with severe early-onset obesity fully reversed by leptin replacement. Proof of concept for the ob/ob mouse phenotype in humans.

Unger 1995. Named lipotoxicity: when adipose tissue can no longer contain lipid, overflow to the pancreas impairs beta-cell function and initiates type 2 diabetes.

Bjorntorp 1990. The portal hypothesis: visceral fat drains FFA directly to the liver, driving hepatic insulin resistance. Central obesity as a cardiometabolic risk factor explained at the level of anatomy and physiology.