T cells accumulate in non-diabetic islets during ageing

Background: The resident immune population of pancreatic islets has roles in islet development, beta cell physiology, and the pathology of diabetes. These roles have largely been attributed to islet macrophages, comprising 90% of islet immune cells (in the absence of islet autoimmunity), and, in the case of type 1 diabetes, to infiltrating autoreactive T cells. In adipose, tissue-resident and recruited T and B cells have been implicated in the development of insulin resistance during diet-induced obesity and ageing, but whether this is paralleled in the pancreatic islets is not known. Here, we investigated the non-macrophage component of resident islet immune cells in islets isolated from C57BL/6 J male mice during ageing (3 to 24 months of age) and following similar weight gain achieved by 12 weeks of 60% high fat diet. Immune cells were also examined by flow cytometry in cadaveric non-diabetic human islets. Results: Immune cells comprised 2.7 ± 1.3% of total islet cells in non-diabetic mouse islets, and 2.3 ± 1.7% of total islet cells in non-diabetic human islets. In 3-month old mice on standard diet, B and T cells each comprised approximately 2–4% of the total islet immune cell compartment, and approximately 0.1% of total islet cells. A similar amount of T cells were present in non-diabetic human islets. The majority of islet T cells expressed the αβ T cell receptor, and were comprised of CD8-positive, CD4-positive, and regulatory T cells, with a minor population of γδ T cells. Interestingly, the number of islet T cells increased linearly (R² = 0.9902) with age from 0.10 ± 0.05% (3 months) to 0.38 ± 0.11% (24 months) of islet cells. This increase was uncoupled from body weight, and was not phenocopied by a degree similar weight gain induced by high fat diet in mice. Conclusions: This study reveals that T cells are a part of the normal islet immune population in mouse and human islets, and accumulate in islets during ageing in a body weight-independent manner. Though comprising only a small subset of the immune cells within islets, islet T cells may play a role in the physiology of islet ageing.Medicine, Faculty ofOther UBCNon UBCSurgery, Department ofReviewedFacult

Loss of <i>Malat1</i> does not modify age- or diet-induced adipose tissue accretion and insulin resistance in mice

<div><p>Several studies have suggested that signals emerging from white adipose tissue can contribute to the control of longevity. In turn, aging is associated with perturbed regulation and partitioning of fat depots and insulin resistance. However, the exact mechanisms involved in these relationships remain undetermined. Using RAP-PCR on adipose tissue of young and old male mice coupled with qPCR validation, we have uncovered the long non-coding RNA <i>Malat1</i> as a gene robustly downregulated in visceral white adipose tissue (vWAT) during normal aging in male mice and men. Reductions in <i>Malat1</i> expression in subcutaneous WAT (scWAT) were also observed in genetic (<i>ob</i> and <i>db</i>) as well as diet-induced models of obesity. Based on these findings, <i>Malat1</i>+/+ and <i>Malat1</i>-/- mouse littermates were thus probed to detect whether loss of <i>Malat1</i> would impact age or diet-induced gain in fat mass and development of glucose intolerance. Contrary to this hypothesis, male and female <i>Malat1</i>-deficient mice gained as much weight, and developed insulin resistance to a similar extent as their <i>Malat1</i>+/+ littermates when studied up to eight months old on regular chow or a high-fat, high-sucrose diet. Moreover, we observed no marked difference in oxygen consumption, food intake, or lipid profiles between <i>Malat1</i>+/+ and <i>Malat1</i>-/- mice. Therefore, we conclude that the overall metabolic impact of the absence of <i>Malat1</i> on adipose tissue accretion and glucose intolerance is either physiologically not relevant upon aging and obesity, or that it is masked by as yet unknown compensatory mechanisms.</p></div

Aging is associated with a reduction in <i>Malat1</i> levels in visceral adipose tissue in mice and men.

<p>(A) Expression levels of <i>Malat1</i> in skeletal muscle, epididymal (visceral—vWAT) inguinal (subcutaneous—scWAT) white adipose tissue, and interscapular brown adipose tissue (BAT) of 4, 12 or 24 months old male C57BL/6J mice (n = 12–14). * indicates a significant difference compared with the 4 months old group (<i>p</i> < 0.05). (B) Expression levels of <i>Malat1</i> in visceral (omental) and subcutaneous white adipose tissue of men on average 23 (young), 40 (middle-aged), or 59 (old) ± 1 years old (n = 7–10). * indicates a significant difference compared with younger group (<i>p</i> < 0.05). (C-D) <i>Malat1</i> (C) and <i>mascRNA</i> (D) expression levels in cells of the stroma vascular fraction (SVF) or adipocyte freshly collagenase-isolated from vWAT of young and old male mice described in A. n = 3. * indicates a significant difference compared with the 4 months old group (<i>p</i> < 0.05).</p

Glucose and lipid levels in diet-induced obese <i>Malat1</i>+/+ and <i>Malat1</i>-/- mice.

<p>Plasma levels of glucose (A), triglycerides (B) and cholesterol (C) were quantified after overnight fasting in male and female 9 months old <i>Malat1</i>+/+ and <i>Malat1</i>-/- mice fed a high-fat, high-sucrose diet since the age of 11 weeks. (n = 9–10).</p

White adipose tissue histology in <i>Malat1</i>+/+ and <i>Malat1</i>-/- mice.

<p>Representative images of vWAT (A) and scWAT (C) and respective relative proportion of adipocytes as function of size (B-D). For adipocyte size, 934 and 1571 adipocytes in vWAT and 962 and 1328 in scWAT were analyzed within histological slides of two <i>Malat1</i>+/+ and 2 <i>Malat1</i>-/- 3 months old mice, respectively. In panels A and C, magnification is 200 X.</p

Absence of <i>Malat1</i> does not influence age-induced insulin resistance.

<p>(A) Glucose tolerance test in 2 (left) or 7.5 (right) months old male <i>Malat1</i>+/+ and <i>Malat1</i>-/- mice fed a chow diet. (n = 9–13). (B) Insulin sensitivity test in 2 (left) or 8 (right) months old male <i>Malat1</i>+/+ and <i>Malat1</i>-/- mice fed a chow diet. (n = 8–13). (C) Glucose tolerance test in 2 (left) or 7.5 (right) months old female <i>Malat1</i>+/+ and <i>Malat1</i>-/- mice fed a chow diet. (n = 6–10).</p

Absence of Malat1 does not influence diet-induced glucose intolerance.

<p>(A) Glucose tolerance test before (left) or after six months (right) of a high-fat, high-sucrose feeding regimen in male Malat1+/+ and Malat1-/- mice. (n = 6–10). (B) Glucose tolerance test before (left) or after six months (right) of a high-fat, high-sucrose feeding regimen in female Malat1+/+ and Malat1-/- mice. (n = 7–8).</p