Hypoxia in Human Obesity: New Insights from Inflammation towards Insulin Resistance-A Narrative Review

Abstract

Insulin resistance (IR), marked by reduced cellular responsiveness to insulin, and obesity, defined by the excessive accumulation of adipose tissue, are two intertwined conditions that significantly contribute to the global burden of cardiometabolic diseases. Adipose tissue, beyond merely storing triglycerides, acts as an active producer of biomolecules. In obesity, as adipose tissue undergoes hypertrophy, it becomes dysfunctional, altering the release of adipocyte-derived factors, known as adipokines. This dysfunction promotes low-grade chronic inflammation, exacerbates IR, and creates a hyperglycemic, proatherogenic, and prothrombotic environment. However, the fundamental cause of these phenomena remains unclear. This narrative review points to hypoxia as a critical trigger for the molecular changes associated with fat accumulation, particularly within visceral adipose tissue (VAT). The activation of hypoxia-inducible factor-1 (HIF-1), a transcription factor that regulates homeostatic responses to low oxygen levels, initiates a series of molecular events in VAT, leading to the aberrant release of adipokines, many of which are still unexplored, and potentially affecting peripheral insulin sensitivity. Recent discoveries have highlighted the role of hypoxia and miRNA-128 in regulating the insulin receptor in visceral adipocytes, contributing to their dysfunctional behavior, including impaired glucose uptake. Understanding the complex interplay between adipose tissue hypoxia, dysfunction, inflammation, and IR in obesity is essential for developing innovative, targeted therapeutic strategies.

Keywords: adipokine; adipose tissue; hypoxia; inflammation; insulin resistance; micro-RNA.

Figure 1

The key steps and effects of physiological insulin signaling in sensitive adipocytes. INSR, insulin receptor; IGF1R, IFG1 receptor; IRS1/2, insulin receptor substrates 1 and 2; PDK1, 3-phosphoinositide-dependent protein kinase 1; mTORC2 mammalian target of rapamycin complex 2; TSC2, tuberous sclerosis 2; GSK3, glycogen synthase kinase-3; AS160, Akt substrate of 160 kDa; mTORC1 mammalian target of rapamycin complex 1; GLUT4, glucose transporter 4.

Figure 2

Morphological and functional changes occurring in mature visceral adipocytes following transition into a hypertrophic state, as commonly observed in obesity. This transition involves an increase in cell size and a decrease in oxygen (O₂) tension within the cells, ultimately leading to a hypoxic environment. In hypoxic adipocytes, overexpression of miR-128 promotes the degradation of INSR mRNA, leading to reduced production of INSR protein and subsequent development of IR.

Figure 3

The interplay between hypoxia, inflammation, and metabolic dysregulation at the core of the pathogenesis of obesity-related IR. As obesity progresses and fat mass increases, visceral adipocytes enlarge and become increasingly distant from capillary blood vessels, leading to hypoxia and subsequent cellular dysfunction. Hypoxic adipocytes exhibit reduced expression and activity of the INSR, which impairs the translocation of the insulin-responsive glucose transporter GLUT4 to the plasma membrane, reducing glucose uptake. Dysfunctional adipocytes also release an abnormal pattern of pro-inflammatory adipokines and cytokines into the extracellular milieu and the circulatory system. The aberrant biosynthesis and secretion of these pro-inflammatory biomolecules are modulated by HIF-1, which is overactivated in hypoxia and partners with other nuclear factors, such as NF-κB, CREB, and HMGA1, to bind to HREs. This dysregulation in adipokine secretion disrupts systemic insulin signaling, particularly affecting skeletal muscle, another primary site for glucose uptake alongside adipose tissue, thereby further impairing whole-body glucose homeostasis. Additionally, the dysfunctional behavior of hypoxic adipocytes promotes the infiltration and activation of macrophages within visceral adipose tissue. These macrophages then secrete pro-inflammatory cytokines, reactive oxygen species, and exosomal miRNAs, intensifying both local and systemic inflammation. This pathological interplay between adipocytes and immune cells contributes to the development of IR, hyperglycemia, and the onset and progression of atherosclerosis in obese individuals.