Abstract

Obesity-driven type 2 diabetes is a multifactorial metabolic disorder in which dysfunctional inter-organ 
communication particularly between adipose tissue and skeletal muscle plays a pivotal role. Adipokines and 
myokines are hormone-like factors produced by adipocytes and myocytes, respectively, that regulate energy 
homeostasis, insulin sensitivity, inflammation, and substrate metabolism. In obesity, adipose tissue secretes a 
proinflammatory adipokine profile (e.g., increased leptin resistance, resistin, visfatin, and decreased adiponectin) 
while skeletal muscle myokine tone shifts in ways that can exacerbate or ameliorate insulin resistance (e.g., 
irisin, IL-6, myostatin). Natural products plant polyphenols, flavonoids, terpenoids, alkaloids, and bioactive 
peptides exert pleiotropic effects on these signaling molecules and their downstream pathways. This review 
synthesizes mechanistic and translational evidence for natural product modulation of adipokines and myokines, 
examining molecular targets, preclinical efficacy, human trial data where available, and the pharmacological and 
safety challenges of translating nutraceutical interventions into clinical practice. We highlight how select 
natural molecules restore adipokine balance, enhance myokine-mediated insulin-sensitizing effects, and 
attenuate chronic inflammation, thereby offering adjunctive therapeutic potential for obesity-associated 
diabetes. Finally, gaps in evidence, methodological limitations in current studies, and priorities for future 
research standardization, dosing, bioavailability improvement, and rigorous clinical trials are discussed. The 
goal is to provide a coherent, mechanistic, and pragmatic framework for researchers and clinicians exploring 
natural product strategies to rebalance adipose-muscle cross-talk and mitigate metabolic disease progression. 
Keywords: adipokines, myokines, natural products, obesity, type 2 diabetes