Adipose Cell Size and Regional Fat Deposition as Predictors of Metabolic Response to Overfeeding in Insulin-Resistant and Insulin-Sensitive Humans
2016; 65 (5): 1245-1254
Obesity is associated with insulin resistance (IR), but significant variability exists between similarly-obese individuals, pointing to qualitative characteristics of body fat as potential mediators. To test the hypothesis that obese, insulin-sensitive (IS) individuals possess adaptive adipose cell/tissue responses, we measured subcutaneous adipose cell size, insulin-suppression-of lipolysis, and regional fat responses to short-term overfeeding in BMI-matched overweight/obese individuals classified as IS or IR. At baseline, IR subjects exhibited significantly-greater visceral adipose tissue(VAT), intrahepatic lipid(IHL), plasma FFAs , adipose cell diameter, and %small adipose cells. With weight gain (3.1+1.4 kg), IR subjects demonstrated no significant change in adipose cell size, VAT, or insulin-suppression-of lipolysis, and only 8% worsening of insulin-mediated glucose uptake (IMGU).Alternatively, IS subjects demonstrated significant adipose cell enlargement, decrease in %small adipose cells, increase in VAT, IHL, lipolysis, 45% worsening of IMGU, and decreased expression of lipid metabolism genes. Smaller baseline adipose cell size and greater enlargement with weight gain predicted decline in IMGU, as did increase in IHL, VAT, and decrease in insulin-suppression-of lipolysis. Weight gain in IS humans causes maladaptive changes in adipose cells, regional fat distribution, and insulin resistance. The correlation between worsening insulin resistance and changes in adipose cell size, VAT, IHL, and insulin-suppression-of lipolysis highlight these factors as potential mediators between obesity and insulin resistance.
View details for DOI 10.2337/db15-1213
View details for Web of Science ID 000375028000015
View details for PubMedID 26884438
Pasireotide Induced Adrenal Insufficiency.
We report the case of secondary adrenal insufficiency in a 56-year-old woman with a history of post-Roux-en-Y gastric bypass hyperinsulinemic hypoglycemia, undergoing experimental treatment with pasireotide. This article is protected by copyright. All rights reserved.
View details for DOI 10.1111/cen.13016
View details for PubMedID 26733356
In vivo (H2O)-H-2 administration reveals impaired triglyceride storage in adipose tissue of insulin-resistant humans
JOURNAL OF LIPID RESEARCH
2015; 56 (2): 435-439
Indirect evidence suggests that impaired triglyceride storage in the subcutaneous fat depot contributes to the development of insulin resistance via lipotoxicity. We directly tested this hypothesis by measuring, in vivo, TG synthesis, de novo lipogenesis (DNL), adipocyte proliferation, and insulin suppression of lipolysis in subcutaneous adipose tissue of BMI-matched individuals classified as insulin resistant (IR) or insulin sensitive (IS). Nondiabetic, moderately obese subjects with BMI 25-35 kg/m(2), classified as IR or IS by the modified insulin suppression test, consumed deuterated water ((2)H2O) for 4 weeks. Deuterium incorporation into glycerol, palmitate, and DNA indicated TG synthesis, DNL, and adipocyte proliferation, respectively. Net TG synthesis and DNL in adipose cells were significantly lower in IR as compared with IS subjects, whereas adipocyte proliferation did not differ significantly. Plasma FFAs measured during an insulin suppression test were 2.5-fold higher in IR subjects, indicating resistance to insulin suppression of lipolysis. Adipose TG synthesis correlated directly with DNL but not with proliferation. These results provide direct in vivo evidence for impaired TG storage in subcutaneous adipose tissue of IR as compared with IS. Relative inability to store TG in the subcutaneous depot may represent a mechanism contributing to the development of insulin resistance in the setting of obesity.
View details for DOI 10.1194/jlr.M052860
View details for Web of Science ID 000348905000022
The Use of Gastrostomy Tube for the Long-Term Remission of Hyperinsulinemic Hypoglycemia After Roux-en-y Gastric Bypass: A Case Report
AACE Clinical Case Reports: Spring 2015
2015; 1 (2): e84-e87
View details for DOI 10.4158/EP14218
The Integrative Human Microbiome Project: Dynamic Analysis of Microbiome-Host Omics Profiles during Periods of Human Health and Disease
CELL HOST & MICROBE
2014; 16 (3): 276-289
Much has been learned about the diversity and distribution of human-associated microbial communities, but we still know little about the biology of the microbiome, how it interacts with the host, and how the host responds to its resident microbiota. The Integrative Human Microbiome Project (iHMP, http://hmp2.org), the second phase of the NIH Human Microbiome Project, will study these interactions by analyzing microbiome and host activities in longitudinal studies of disease-specific cohorts and by creating integrated data sets of microbiome and host functional properties. These data sets will serve as experimental test beds to evaluate new models, methods, and analyses on the interactions of host and microbiome. Here we describe the three models of microbiome-associated human conditions, on the dynamics of preterm birth, inflammatory bowel disease, and type 2 diabetes, and their underlying hypotheses, as well as the multi-omic data types to be collected, integrated, and distributed through public repositories as a community resource.
View details for DOI 10.1016/j.chom.2014.08.014
View details for Web of Science ID 000342057000006
View details for PubMedID 25211071
Notch Oncoproteins depend on gamma-secretase/presenilin activity for processing and function
JOURNAL OF BIOLOGICAL CHEMISTRY
2004; 279 (29): 30771-30780
During normal development Notch receptor signaling is important in regulating numerous cell fate decisions. Mutations that truncate the extracellular domain of Notch receptors can cause aberrant signaling and promote unregulated cell growth. We have examined two types of truncated Notch oncoproteins that arise from proviral insertion into the Notch4 gene (Notch4/int-3) or a chromosomal translocation involving the Notch1 gene (TAN-1). Both Notch4/int-3 and TAN-1 oncoproteins lack most or all of their ectodomain. Normal Notch signaling requires gamma-secretase/presenilin-mediated proteolytic processing, but whether Notch oncoproteins are also dependent on gamma-secretase/presenilin activity is not known. We demonstrate that Notch4/int-3-induced activation of the downstream transcription factor, CSL, is abrogated in cells deficient in presenilins or treated with a pharmacological inhibitor of gamma-secretase/presenilins. Furthermore, we find that both Notch4/int-3 and TAN-1 accumulate at the cell surface, where presenilin-dependent cleavage occurs, when gamma-secretase/presenilin activity is inhibited. gamma-Secretase/presenilin inhibition effectively blocks cellular responses to Notch4/int-3, but not TAN-1, apparently because some TAN-1 polypeptides lack transmembrane domains and do not require gamma-secretase/presenilin activity for nuclear access. These studies highlight potential uses and limitations of gamma-secretase/presenilin inhibitors in targeted therapy of Notch-related neoplasms.
View details for DOI 10.1074/jbc.M309252200
View details for Web of Science ID 000222531900108
View details for PubMedID 15123653