Obesity induces catecholamine resistance in adipose tissue, which impairs lipolysis and reduces energy expenditure. Here, we show that phillyrin attenuates catecholamine resistance in obese adipose tissue in association with suppression of the IL-6R–STAT3–ERK1/2 positive feedback loop. In high-fat diet (HFD)-induced obese mice, low-dose phillyrin (1 mg/kg) significantly elevated 24-h energy expenditure and oxygen consumption. It also markedly enhanced β3-adrenergic-stimulated lipolysis in both visceral and subcutaneous adipose depots, accompanied by increased phosphorylation of hormone-sensitive lipase (HSL) at Ser660. Furthermore, phillyrin effectively rescued IL-6-induced catecholamine resistance both in vitro and in vivo. Mechanistically, phillyrin downregulated IL-6Rα expression and suppressed the phosphorylation of STAT3 (Tyr705) and ERK1/2, consistent with attenuation of the self-amplifying inflammatory loop that desensitizes β-adrenergic signaling. These findings implicate the IL-6R–STAT3–ERK1/2 positive feedback loop as a mediator of obesity-associated catecholamine resistance and support phillyrin as a promising therapeutic candidate for improving lipolytic capacity and metabolic homeostasis in obesity.
Unlike mammals, birds lack canonical brown adipose tissue and the UCP1 gene, yet exhibit UCP1-independent non-shivering thermogenesis (NST). In vitro, embryonic chicken mesenchymal cells differentiate into avian brown adipocyte-like cells (ABALCs) with multilocular lipid droplets, elevated mitochondrial density, and upregulated PGC-1α and PPARγ, activating a transfected mouse UCP1 promoter despite endogenous UCP1 loss. In vivo, gradual cold acclimatization or triiodothyronine (T3) induces beige-like adipocytes enriched in mitochondria within the subcutaneous neck depot (“neck warmer”), with increased avian uncoupling protein (avUCP), CIDEA, TBX1, and mitochondrial markers, while abdominal fat remains largely unresponsive. Skeletal muscle is the main site of NST, where SERCA/RyR-mediated calcium cycling and avUCP/ANT-associated mitochondrial uncoupling are candidate mechanisms; because avUCP is multifunctional (heat, redox and fuel handling), its expression is not by itself a read-out of heat output. Nutritional and microbial interventions—including polyunsaturated fatty acids, capsaicin, succinate, bile acids, and probiotics—have been associated with altered lipid metabolism and reduced visceral adiposity, although direct links to quantifiable heat production remain unestablished and non-thermogenic mechanisms (lipid digestion, hepatic lipogenesis, feed intake, inflammation) have not been excluded. Collectively, the evidence is consistent with, but does not yet prove, a conserved, multi-organ thermogenic metabolic network (TMN) in birds in which skeletal muscle predominates. Exploiting this latent capacity offers a conceptual framework for nutritional and management strategies to mitigate excessive fat deposition and enhance thermal resilience in commercial broilers, although the energetic trade-offs with growth and feed efficiency remain to be resolved. A structured roadmap integrating nutritional, microbial, environmental, and genetic approaches is proposed to test, and if validated to harness, the TMN for sustainable production.
Metabolic syndrome (MetS), conventionally associated with obesity, also occurs in individuals with a normal body mass index (BMI), revealing an important discordance between body weight and metabolic health. This phenotype, variably described as normal-weight metabolic syndrome (NWMS), metabolically obese normal weight (MONW), or metabolically unhealthy normal weight (MUNW), is characterized by metabolic abnormalities despite the absence of generalized obesity. Reported prevalence varies substantially across populations because of heterogeneity in phenotype definitions, BMI thresholds, metabolic criteria, and population characteristics, and the global burden remains uncertain. Nevertheless, affected individuals have an increased risk of type 2 diabetes and cardiovascular disease compared with metabolically healthy normal-weight individuals. This review critically synthesizes current evidence on the epidemiology, clinical manifestations, diagnostic approaches, and pathogenic mechanisms of NWMS. Visceral and ectopic adiposity, insulin resistance, adipose tissue dysfunction, and chronic low-grade inflammation represent the most consistently supported pathogenic pathways. In contrast, gut microbiota dysbiosis, oxidative stress, ferroptosis, and related molecular processes remain emerging mechanisms with limited evidence specific to normal-weight populations. Recognition of metabolic risk beyond BMI is therefore important, particularly in susceptible populations. A risk-based approach incorporating conventional metabolic assessment, measures of central adiposity, and selective body-composition assessment may improve identification of affected individuals. Harmonized phenotype definitions and studies across geographically and ethnically diverse populations are needed to define the global burden and inform targeted prevention and management strategies.
