Aims/hypothesisA subset of obese individuals remains insulin sensitive by mechanisms as yet unclear. The hypothesis that maintenance of normal subcutaneous (SC) adipogenesis accounts, at least partially, for this protective phenotype and whether it can be abrogated by chronic exposure to IL-6 was investigated.MethodsAdipose tissue biopsies were collected from insulin-sensitive (IS) and insulin-resistant (IR) individuals undergoing weight-reduction surgery. Adipocyte size, pre-adipocyte proportion of stromal vascular fraction (SVF)-derived cells, adipogenic capacity and gene expression profiles of isolated pre-adipocytes were determined, along with local in vitro IL-6 secretion. Adipogenic capacity was further assessed in response to exogenous IL-6 application.ResultsDespite being equally obese, IR individuals had significantly lower plasma leptin and adiponectin levels and higher IL-6 levels compared with age-matched IS counterparts. Elevated systemic IL-6 in IR individuals was associated with hyperplasia of adipose tissue-derived SVF cells, despite higher frequency of hypertrophied adipocytes. SC pre-adipocytes from these tissues exhibited lower adipogenic capacity accompanied by downregulation of PPARγ (also known as PPARG) and CEBPα (also known as CEBPA) and upregulation of GATA3 expression. Impaired adipogenesis in IR individuals was further associated with increased adipose secretion of IL-6. Treatment of IS-derived SC pre-adipocytes with IL-6 reduced their adipogenic capacity to levels of the IR group.Conclusions/interpretationObesity-associated insulin resistance is marked by impaired SC adipogenesis, mediated, at least in a subset of individuals, by elevated local levels of IL-6. Understanding the molecular mechanisms underlying reduced adipogenic capacity in IR individuals could help target appropriate therapeutic strategies aimed at those at greatest risk of insulin resistance and type 2 diabetes mellitus.

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BackgroundLaparoscopic sleeve gastrectomy (LSG) is a common surgical therapeutic option for obese patients, with debate about the value of routine histopathologic examination of LSG specimens. We assessed the following: prevalence of different histopathologic changes in LSG specimens, risk factors associated with premalignant and with frequent histopathologic changes, and whether routine histopathologic examination is warranted for LSG patients with nonsignificant clinical history.MethodsRetrospective review of records of all LSG patients operated upon at Hamad General Hospital, Qatar (February 2011–July 2014, n = 1555), was conducted. Risk factors (age, BMI, gender, and Helicobacter pylori) were assessed in relation to specific abnormal histopathologic changes.ResultsMean age and BMI of our sample were 35.5 years and 46.8, respectively. Females comprised 69.7% of the sample. Normal histopathologic specimens comprised 52% of the sample. The most common histopathologic changes were chronic inactive gastritis (33%), chronic active gastritis (6.8%), follicular gastritis (2.7%), and lymphoid aggregates (2.2%). We observed rare histopathology in 3.3% of the sample [e.g., intestinal metaplasia and gastrointestinal stromal tumor (GIST)]. Older age was associated with GIST and intestinal metaplasia (P = 0.001 for both). Females were associated with chronic active gastritis (P = 0.003). H. pylori infection was associated with follicular gastritis, lymphoid aggregates, GIST, intestinal metaplasia, and chronic active gastritis (P < 0.001 for each).ConclusionOlder age, H. pylori, and female gender are risk factors for several abnormal histopathologic changes. Histopathologic examination of LSG specimens might harbor significant findings; however, routine histopathologic examination of all LSG specimens, particularly in the absence of suggestive clinical symptoms, is questionable. The association between female gender and chronic active gastritis; and the association between H. pylori infection and GIST are both novel findings that have not been previously reported in the published literature.

ObjectiveObesity-associated impaired fat accumulation in the visceral adipose tissue can lead to ectopic fat deposition and increased risk of insulin resistance and type 2 diabetes mellitus (T2DM). This study investigated whether impaired adipogenesis of omental (OM) adipose tissues and elevated 4-hydroxynonenal (4-HNE) accumulation contribute to this process, and if combined metformin and insulin treatment in T2DM patients could rescue this phenotype.MethodsOM adipose tissues were obtained from forty clinically well characterized obese individuals during weight reduction surgery. Levels of 4-HNE protein adducts, adipocyte size and number of macrophages were determined within these tissues by immunohistochemistry. Adipogenic capacity and gene expression profiles were assessed in preadipocytes derived from these tissues in relation to insulin resistance and in response to 4-HNE, metformin or combined metformin and insulin treatment.ResultsPreadipocytes isolated from insulin resistant (IR) and T2DM individuals exhibited lower adipogenesis, marked by upregulation of anti-adipogenic genes, compared to preadipocytes derived from insulin sensitive (IS) individuals. Impaired adipogenesis was also associated with increased 4-HNE levels, smaller adipocytes and greater macrophage presence in the adipose tissues. Within the T2DM group, preadipocytes from combined metformin and insulin treated subset showed better in vitro adipogenesis compared to metformin alone, which was associated with less presence of macrophages and 4-HNE in the adipose tissues. Treatment of preadipocytes in vitro with 4-HNE reduced their adipogenesis and increased proliferation, even in the presence of metformin, which was partially rescued by the presence of insulin.ConclusionThis study reveals involvement of 4-HNE in the impaired OM adipogenesis-associated with insulin resistance and T2DM and provides a proof of concept that this impairment can be reversed by the synergistic action of insulin and metformin. Further studies are needed to evaluate involvement of 4-HNE in metabolically impaired abdominal adipogenesis and to confirm benefits of combined metformin-insulin therapy in T2DM patients.