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

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, developing hyperinsulinemia. In the absence of postprandial insulin, adrenergic stimulation causes cyclic AMP (cAMP)-dependent phosphorylation of both perilipin, which coats the adipocyte lipid droplet, and hormone-sensitive lipase, allowing hydrolytic release of fatty acids from triglyceride for their use as fuel elsewhere (7). Insulin exerts antilipolytic activity by activating PDE3B, a cAMP phosphodiesterase, as well as promoting reesterification of fatty acids to newly generated glycerol 3-phosphate. Thus, the visceral focus of adipose insulin resistance contributes strongly to another feature of the metabolic syndrome, nonalcoholic fatty liver disease, via increased return of hydrolyzed fatty acid to the portal circulation (8). Increased lypolysis owing to adipocyte insulin resistance may also contribute to muscle insulin resistance and impairment of -cell secretory function via lipotoxicity (2,3). A somewhat recently appreciated feature of the expanding adipose compartment of obesity is the occurrence of localized hypoxia (reviewed in ref. 9). The presence of hypoxic regions within adipose tissues of obese rodents has been demonstrated by anaerobic adductive chemistry in vivo, increased local lactate concentrations, and specific hypoperfusion of adipose tissue (10). The presence of hypoxia in human adipose tissue is at least strongly implied, given the similar hypoperfusion that is characteristic of human obesity (9). The principle sensor and mediator of the adipocyte response to hypoxia is hypoxia-inducible factor (HIF)-1, a heterodimeric ( / ) transcription factor, of which the -subunit (HIF-1 or HIF-2 ) is directly regulated by oxygen tension. HIF-1 protein is expressed at higher levels in adipose tissue of obese rodents, and its mRNA has been reported to be upregulated in fat and infiltrating macrophages of obese humans (9). Under normoxic conditions, HIF-1 undergoes prolyl hydroxylation and is degraded by the ubuiquitin/proteasomal route; by contrast, in hypoxia, its hydroxylation is disfavored, allowing newly synthesized HIF-1 to accumulate, complex with its -subunit, and activate gene transcription. At some promoters, at least, this takes place in cooperation with cAMP-responsive element–binding protein (CREB) and its coactivator p300. In general, the transcription of HIF-1 target genes serves to alter the local microenvironment by promoting angiogenesis (vascular endothelial growth factor), tissue remodeling (matrix metalloproteinases), and inflammation (interleukin-6, plasminogen activator inhibitor-1, and, perhaps, tumor necrosis factor). As with HIF-1 itself, genes in the last category may also be upregulated in nearby macrophages, which cluster about dying adipocytes; this suggests a potentiation of localized inflammation by the hypoxic microenvironment (2,10). Another class of HIF-1 target genes likely promotes adipocyte survival via adaptation to anaerobic metabolism. Among these are pyruvate dehydrogenase kinase—which shunts acetyl-CoA away from mitochondrial oxidation via conversion into lactate—and GLUT1, which promotes insulinindependent uptake of glucose. Importantly, production of the insulin-sensitizing adipokine adiponectin/Acrp30 is also decreased during hypoxia, paralleling the decrease in serum adiponectin levels in human obesity. Thus, activation of the HIF-1 program seems likely to worsen inflammation, impair healthy adipose endocrine function, and contribute to whole-body insulin resistance. Surprisingly, a relationship between hypoxia and insulin resistance within adipocytes per se has not, until now, From the Howard Hughes Medical Institute and Children’s Hospital, Boston, Massachusetts. Corresponding author: Morris F. White, [email protected]. DOI: 10.2337/db08-1517 © 2009 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by -nc-nd/3.0/ for details. See accompanying original article, p. 95. COMMENTARY