Breathing Room: The (Un)Natural History of Adipose Microhypoxia and Insulin Resistance

  1. Morris F. White
  1. From the Howard Hughes Medical Institute and Children's Hospital, Boston, Massachusetts
  1. Corresponding author: Morris F. White, morris.white{at}

The basis for the clustering of obesity with insulin resistance, type 2 diabetes, and related pathologies of the metabolic syndrome is complex but involves altered metabolic function and substrate flow both within and between insulin-responsive fat, muscle, and liver tissues (1,2). Since the discovery of leptin in the 1990s, the focus on the normal endocrine and (more recently) the pathological inflammatory roles of adipose tissue has been rewarded with ever-accelerating advancements in our understanding of metabolic disease. However, it is worth noting that endocrine/inflammatory dysfunction of adipose tissue does not naturally occur independently of insulin resistance within adipocytes themselves. Rather, both naturally emerge from the history of the expanding adipose compartment in obesity (2,3). While a complete description of adipose tissue expansion is lacking, an increase in size of existing adipocytes (hypertrophy) appears to predominate in early stages, followed only later by the appearance of smaller, apparently newer adipocytes (hyperplasia) (4).

A key element in diagnosis of the metabolic syndrome, as well as an important diabetes risk factor, is expanded central, or visceral, adiposity. For example, stepwise and multiple regression models involving MRI-determined masses of all adipose depots— controlled for age, obesity, and serum triglyceride and nonesterified fatty acid levels—identify visceral fat as a significant risk factor for insulin resistance (5). Moreover, human visceral adipocytes examined ex vivo have been known for some time to be insulin resistant relative to subcutaneous adipocytes. (For one example, see ref. 6). The basis for this resistance is complex but likely involves increased exposure to cortisol, adrenergic stimulation, and, perhaps, …

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