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Human adipose cells in vitro are either refractory or responsive to insulin, reflecting host metabolic state.

Lizunov VA, Stenkula KG, Blank PS, Troy A, Lee JP, Skarulis MC, Cushman SW, Zimmerberg J - PLoS ONE (2015)

Bottom Line: Two statistically-defined populations best describe the observed cellular heterogeneity, representing the fractions of refractive and responsive adipose cells.Thus, a two-component model best describes the relationship between cellular refractory fraction and subject SI.Since isolated cells exhibit these different response characteristics in the presence of constant culture conditions and milieu, we suggest that a physiological switching mechanism at the adipose cellular level ultimately drives systemic SI.

View Article: PubMed Central - PubMed

Affiliation: Program in Physical Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States of America.

ABSTRACT
While intercellular communication processes are frequently characterized by switch-like transitions, the endocrine system, including the adipose tissue response to insulin, has been characterized by graded responses. Yet here individual cells from adipose tissue biopsies are best described by a switch-like transition between the basal and insulin-stimulated states for the trafficking of the glucose transporter GLUT4. Two statistically-defined populations best describe the observed cellular heterogeneity, representing the fractions of refractive and responsive adipose cells. Furthermore, subjects exhibiting high systemic insulin sensitivity indices (SI) have high fractions of responsive adipose cells in vitro, while subjects exhibiting decreasing SI have increasing fractions of refractory cells in vitro. Thus, a two-component model best describes the relationship between cellular refractory fraction and subject SI. Since isolated cells exhibit these different response characteristics in the presence of constant culture conditions and milieu, we suggest that a physiological switching mechanism at the adipose cellular level ultimately drives systemic SI.

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GSV mobility and Fusion rates do not correlate with adipocyte size.Histogram of estimated cell sizes obtained from TIRF projection (a). Mobility and fusion rates as a function of estimated cell sizes (b and c). The slopes of the linear fits for both mobility and fusion in the basal (black) and insulin stimulated (red) are not significantly different from zero indicating there is no correlation with adipocyte size.
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pone.0119291.g007: GSV mobility and Fusion rates do not correlate with adipocyte size.Histogram of estimated cell sizes obtained from TIRF projection (a). Mobility and fusion rates as a function of estimated cell sizes (b and c). The slopes of the linear fits for both mobility and fusion in the basal (black) and insulin stimulated (red) are not significantly different from zero indicating there is no correlation with adipocyte size.

Mentions: To determine a mechanism giving rise to the cellular bimodal response described here, we first thought of the well-documented heterogeneity in adipose cell size [13, 14]. However, while we did not systematically study adipose cells of widely different size, we rule out this possibility because among the cells we did study in our experiments, cell size distribution was unimodal (Fig. 7), with no correlation observed between the measured GSV trafficking and fusion parameters, and the estimated cell size (Fig. 5 B,C). We cannot at this time judge other parameters of cellular heterogeneity, such as cell. age and/or the recently described potential for trans-differentiation from white to beige adipose cells [15]. More likely, in addition to the genetic factors that influence cell physiology, adipose cells in situ are exposed to multiple extracellular factors that bind to cell surface receptors, such as hormones and cytokines [16, 17]. Metabolites that enter cells directly, such as glucose and fatty acids, may also have a role [4, 18]. The finding that glucose entry regulates organelle trafficking by the covalent attachment of a glucose moiety to an intracellular protein regulator of the specific microtubule motor activity in Drosophila, where insulin also functions to stimulate GLUT4 trafficking [19], demonstrates how O-GlcNAc transferase could operate in adipose cells to provide a primary defect [20]. Furthermore, heterogeneity may occur as a consequence of interactions between the immune system and individual adipose cells; immune cells present in adipose tissue have been shown to play dual functions as they are capable of both inducing local insulin resistance and increasing insulin-sensitivity of adipose cells [21, 22]. Nevertheless, whatever the factor(s) may be, adipose cells in culture retain a “memory” of the physiological state of the subject from which they are removed, consistent with the concept that the observed cellular characteristics may be a driving force in systemic physiology rather than a consequence.


Human adipose cells in vitro are either refractory or responsive to insulin, reflecting host metabolic state.

Lizunov VA, Stenkula KG, Blank PS, Troy A, Lee JP, Skarulis MC, Cushman SW, Zimmerberg J - PLoS ONE (2015)

GSV mobility and Fusion rates do not correlate with adipocyte size.Histogram of estimated cell sizes obtained from TIRF projection (a). Mobility and fusion rates as a function of estimated cell sizes (b and c). The slopes of the linear fits for both mobility and fusion in the basal (black) and insulin stimulated (red) are not significantly different from zero indicating there is no correlation with adipocyte size.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4359092&req=5

pone.0119291.g007: GSV mobility and Fusion rates do not correlate with adipocyte size.Histogram of estimated cell sizes obtained from TIRF projection (a). Mobility and fusion rates as a function of estimated cell sizes (b and c). The slopes of the linear fits for both mobility and fusion in the basal (black) and insulin stimulated (red) are not significantly different from zero indicating there is no correlation with adipocyte size.
Mentions: To determine a mechanism giving rise to the cellular bimodal response described here, we first thought of the well-documented heterogeneity in adipose cell size [13, 14]. However, while we did not systematically study adipose cells of widely different size, we rule out this possibility because among the cells we did study in our experiments, cell size distribution was unimodal (Fig. 7), with no correlation observed between the measured GSV trafficking and fusion parameters, and the estimated cell size (Fig. 5 B,C). We cannot at this time judge other parameters of cellular heterogeneity, such as cell. age and/or the recently described potential for trans-differentiation from white to beige adipose cells [15]. More likely, in addition to the genetic factors that influence cell physiology, adipose cells in situ are exposed to multiple extracellular factors that bind to cell surface receptors, such as hormones and cytokines [16, 17]. Metabolites that enter cells directly, such as glucose and fatty acids, may also have a role [4, 18]. The finding that glucose entry regulates organelle trafficking by the covalent attachment of a glucose moiety to an intracellular protein regulator of the specific microtubule motor activity in Drosophila, where insulin also functions to stimulate GLUT4 trafficking [19], demonstrates how O-GlcNAc transferase could operate in adipose cells to provide a primary defect [20]. Furthermore, heterogeneity may occur as a consequence of interactions between the immune system and individual adipose cells; immune cells present in adipose tissue have been shown to play dual functions as they are capable of both inducing local insulin resistance and increasing insulin-sensitivity of adipose cells [21, 22]. Nevertheless, whatever the factor(s) may be, adipose cells in culture retain a “memory” of the physiological state of the subject from which they are removed, consistent with the concept that the observed cellular characteristics may be a driving force in systemic physiology rather than a consequence.

Bottom Line: Two statistically-defined populations best describe the observed cellular heterogeneity, representing the fractions of refractive and responsive adipose cells.Thus, a two-component model best describes the relationship between cellular refractory fraction and subject SI.Since isolated cells exhibit these different response characteristics in the presence of constant culture conditions and milieu, we suggest that a physiological switching mechanism at the adipose cellular level ultimately drives systemic SI.

View Article: PubMed Central - PubMed

Affiliation: Program in Physical Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States of America.

ABSTRACT
While intercellular communication processes are frequently characterized by switch-like transitions, the endocrine system, including the adipose tissue response to insulin, has been characterized by graded responses. Yet here individual cells from adipose tissue biopsies are best described by a switch-like transition between the basal and insulin-stimulated states for the trafficking of the glucose transporter GLUT4. Two statistically-defined populations best describe the observed cellular heterogeneity, representing the fractions of refractive and responsive adipose cells. Furthermore, subjects exhibiting high systemic insulin sensitivity indices (SI) have high fractions of responsive adipose cells in vitro, while subjects exhibiting decreasing SI have increasing fractions of refractory cells in vitro. Thus, a two-component model best describes the relationship between cellular refractory fraction and subject SI. Since isolated cells exhibit these different response characteristics in the presence of constant culture conditions and milieu, we suggest that a physiological switching mechanism at the adipose cellular level ultimately drives systemic SI.

Show MeSH
Related in: MedlinePlus