S P E C I A L
F E A T U R E
E d i t o r i a l
Adipocyte Maturation Arrest: A Determinant of
Systemic Insulin Resistance to Glucose Disposal
Nicola Abate
Department of Internal Medicine and Division of Endocrinology and Metabolism at the University of
Texas Medical Branch, Galveston, Texas 77555
A
n environment enriched with an excessive supply
of food and lacking demand for physical activity
requires adaptive response to “buffer” against metabolic imbalance. If utilization of excessive calories fails
to fulfill this goal, deposition of triglyceride in adipose
tissue is the natural barrier against the toxic effects of
lipid and glucose in virtually all cell types (1, 2). Normal
adipose tissue functions will guarantee protection
against lipo- and glucotoxicity. This is accomplished
through adipocyte differentiation from precursor cells
and maturation to triglyceride-loaded adipocytes of
various sizes. If unchanged, this condition will determine progressive increase in body fat content and
weight gain. Different control mechanisms of adipocyte
differentiation and maturation in various adipose tissue
areas are likely responsible for variability in fat distribution between genders and among individuals.
For decades, research has focused on the role of body
fat mass excess, and then fat distribution, on metabolic
complications typically associated with obesity. We
have witnessed a proliferation of literature in support of
the detrimental effects of increased abdominal/truncal
fat mass on glucose and lipid metabolism. Both visceral
and sc abdominal/truncal fat deposition have been associated with systemic insulin resistance (3) and enhanced risk for associated health complications, such as
type 2 diabetes and cardiovascular disease (3– 6). Unfortunately, the clinical implications of this research
have been rather limited. Although body mass index
(BMI) and waist circumference are widely used as measures of fat mass and distribution and have a role in
predicting risk for type 2 diabetes and cardiovascular
disease, their clinical value is evident only when com-
bined with other metabolic abnormalities, such as those
defining the metabolic syndrome (7). Metabolically
healthy obese persons are frequent in our clinics, and
intervention for prevention of cardiovascular disease
and type 2 diabetes in this group is questionable. More
importantly, metabolically unhealthy nonobese persons are not easily identifiable as candidates for preventive treatment, based on fat mass and distribution.
This is particularly evident in ethnic minorities of the
U.S. population, such as the African-Americans, Hispanics, and Asians. Metabolic abnormalities, including
insulin resistance, are more common in these groups at
lower BMI and waist circumferences, compared with
the European descent group (8, 9). Consequently, use of
specific BMI and waist circumference targets have been
suggested for different populations (10), but the overall
result seems to be more confusion both for patients and
physicians on the real value of these measurements.
Given the growing need to optimize our health care
resource allocation into prevention of chronic diseases,
the lack of appropriate tools to identify patients at risk
for the two major health complications of insulin resistance, type 2 diabetes and cardiovascular disease, is of
significance. Recent trends toward research focusing on
adipose tissue function and metabolic complications of
obesity are promising. Adipose tissue function is now
recognized to play a major role in metabolic homeostasis of both lipids and glucose. Identification of biomarkers of adipose tissue dysfunction may provide the much
needed tools to identify a disease status (adiposopathy)
that precedes and is the cause of metabolic complications, such as insulin resistance. Defining an adipose
tissue dysfunction as a disease would be of value for
ISSN Print 0021-972X ISSN Online 1945-7197
Printed in U.S.A.
Copyright © 2012 by The Endocrine Society
doi: 10.1210/jc.2012-1140 Received January 18, 2012. Accepted January 23, 2012.
Abbreviations: BMI, Body mass index; ErbB1, epidermal growth factor receptor-1.
For article see page E329
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J Clin Endocrinol Metab, March 2012, 97(3):760 –763
J Clin Endocrinol Metab, March 2012, 97(3):760 –763
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FIG. 1. Adipocyte maturation regulation can modulate overall caloric “buffering” function of adipose tissue.
regulatory agencies, pharmaceutical companies, and
clinicians who could better focus therapy to the appropriate patient for prevention of adverse health consequences of glucose and lipid metabolism abnormalities,
such as type 2 diabetes and cardiovascular disease.
Increasing numbers of investigators are refocusing
obesity research along these lines. In this issue of the
JCEM, Rogers et al. (11) identified epidermal growth
factor receptor-1 (ErbB1) as a modulator of adipose
tissue function. Using a combination of in vitro and
clinical studies, their results suggest that ErbB1 is involved in promoting triglyceride storage in adipocytes,
perhaps through maintenance of adequate peroxisome
proliferator-activated receptor-␥ activity. Decreased
ErbB1 protein in sc abdominal adipose tissue was
shown in insulin-resistant subjects and in those who
developed type 2 diabetes. The possibility that ErbB1 is
part of a network of regulators of adipocyte maturation
is intriguing and opens an opportunity to better understand the role of defective adipocyte triglyceride synthesis in fat partitioning, lipid toxicity, and systemic
insulin resistance to glucose disposal. Among other candidate mechanisms of adipocyte maturation, the ectonucleotide pyrophosphatase/phosphodiesterase-1 was
recently shown to induce abnormalities in fat partitioning in association with systemic insulin resistance (12). In
both instances, adipocyte maturation arrest can be viewed
as a specific type of adipose tissue dysfunction or “adi-
posopathy” (13) linked to systemic insulin resistance.
Other known types of adiposopathy, which have been
associated with systemic insulin resistance, may or may
not be exclusively related to adipocyte maturation arrest
and include abnormal adipokine production, adipocyte
leptin resistance, and adipose tissue inflammation.
As schematically depicted in Fig. 1, adipocyte maturation arrest can mechanistically provide an explanation for the apparent dissociation between metabolic
health and fat mass/distribution. In the presence of positive caloric balance, increased demand for triglyceride
storage is normally met by compensatory triglyceride
synthesis in maturing adipocytes. In scenario A, adipocytes are fully capable of accommodating fatty acids
derived from lipolysis of triglycerides in circulating lipoproteins; no spillover of fatty acid will occur. Persisting adipocyte triglyceride synthesis unmatched by
lipolysis will lead to progressive increase in body fat
storage until a new level of caloric balance is accomplished. The patient could become overweight, obese,
or even morbidly obese. In these circumstances, plasma
fatty acids are not expected to be elevated, and substrate
supply for ectopic fat deposition would be minimal. This
scenario explains the coexistence of obesity and normal
glucose/lipid metabolism. It is worthwhile mentioning
that this is not an uncommon circumstance and that about
25% of obese adults are estimated to be insulin sensitive
(14). Additionally, according to the National Health and
762
Abate
Adipocyte Maturation Arrest
Nutrition Examination Survey data, 32% of obese adults
have one or less metabolic abnormalities carrying risk for
cardiovascular complications (15).
The other extreme is shown in scenario C of Fig. 1. In
this case, adipocyte maturation arrest will reduce triglyceride storage capacity in adipose tissue. Consequent increase of fatty acid spillover into plasma will increase substrate availability for triglyceride synthesis in other tissues,
such as liver, skeletal muscle, myocardium, or even pancreas (16, 17). The absence of acquired resistance to the
lipogenic effects of insulin in the liver (18) makes this organ a major target of ectopic fat deposition. Consequent
fatty liver actively contributes to systemic abnormalities of
glucose metabolism, dyslipidemia, and various components of the metabolic syndrome (19 –24). Elevated circulating fatty acid contributes to systemic insulin resistance
also by promoting skeletal muscle switch from glucose to
fatty acid utilization (25). Therefore, a common root for
the metabolic cluster of abnormalities we observe in systemic insulin resistance could be identified in the inability
to store new triglyceride (adipocyte maturation arrest) in
conditions of persisting caloric excess. In this scenario,
patients are expected to have insulin resistance shortly
after positive caloric balance has begun, even in the absence of significant weight gain. This would explain the
observation of metabolically unhealthy lean persons.
Most of our patients likely belong to scenario B depicted in Fig. 1. According to this scenario, a defect in
adipocyte maturation can occur at different stages of adipocyte growth. One can envision the possibility of genetic
and metabolic regulator of the threshold at which triglyceride storage may come to a halt in a given adipocyte or
group of adipocytes. The predicted result will be heterogeneity in adipocyte size distribution and degree of fat
mass increase. Once this threshold is achieved, metabolic
complications similar to scenario C will ensue. Importantly, metabolic complications will be observed at any
level of either total or regional fat mass.
Clearly, the studies of Rogers et al. (11) together with
the growing literature on mechanisms of adipose tissue
dysfunction and its link with the pathogenesis of systemic
insulin resistance beg the need for a shift in the focus of
clinical research from fat mass/distribution to adipose tissue function. Translational applications of the proposed
mechanisms of adipocyte maturation arrest have the potential to help clinicians in better identifying patients at
risk for type 2 diabetes and cardiovascular disease. Better
understanding of these mechanisms in relation to systemic
insulin resistance will certainly lead to new therapeutic
opportunities for prevention of these major causes of morbidity and mortality in our population.
J Clin Endocrinol Metab, March 2012, 97(3):760 –763
Acknowledgments
Address all correspondence and requests for reprints to: Nicola
Abate, M.D., 301 University Boulevard, Galveston, Texas
77555-1060. E-mail: [email protected].
This work is supported by National Institutes of Health
Grants RO1-DK072158 and UL1-RR-029876 and Shriners
Hospitals for Children Grant 71007.
Disclosure Summary: The author has nothing to declare.
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