What role do fat cells play in pancreatic tissue?

Abstract

Background: It is now generally accepted that obesity is a major risk factor for type 2 diabetes mellitus (T2DM). Hepatic steatosis in particular, as well as visceral and ectopic fat accumulation within tissues, is associated with the development of the disease. We recently presented the first study on isolated human pancreatic adipocytes and their interaction with islets [Gerst, F., Wagner, R., Kaiser, G., Panse, M., Heni, M., Machann, J., et al., 2017. Metabolic crosstalk between fatty pancreas and fatty liver: effects on local inflammation and insulin secretion. Diabetologia 60(11):2240-2251.]. The results indicate that the function of adipocytes depends on the overall metabolic status in humans which, in turn, differentially affects islet hormone release.

Scope of review: This review summarizes former and recent studies on factors derived from adipocytes and their effects on insulin-secreting β-cells, with particular emphasis on the human pancreas. The adipocyte secretome is discussed with a special focus on its influence on insulin secretion, β-cell survival and apoptotic β-cell death.

Major conclusions: Human pancreatic adipocytes store lipids and release adipokines, metabolites, and pro-inflammatory molecules in response to the overall metabolic, humoral, and neuronal status. The differentially regulated adipocyte secretome impacts on endocrine function, i.e., insulin secretion, β-cell survival and death which interferes with glycemic control. This review attempts to explain why the extent of pancreatic steatosis is associated with reduced insulin secretion in some studies but not in others.

Keywords: Adipocytes; Fatty pancreas; Insulin secretion; Paracrine signalling; Type 2 diabetes mellitus (T2DM); β-cell mass.

Figure 1

Overview of the white adipocyte's secretory activity. Updated and modified version of Figure 1 in [Staiger H, Häring HU. White adipose tissue's humoral mediators of chronic subclinical inflammation. Int. J. Adipose Tissue 1 (2007): 17–23]. Resistin is produced by murine adipocytes only. Abbreviations: ACE – angiotensin-converting enzyme; ANGPTL – angiopoietin-like protein; ANP – atrial natriuretic peptide; Apo – apolipoprotein; ASIP – agouti signaling protein; ASP – acylation-stimulating protein; CETP – cholesteryl ester transfer protein; CXCL – C-X-C motif chemokine; DPP – dipeptidyl peptidase; FGF – fibroblast growth factor; GCSF – granulocyte-colony-stimulating factor; HB-EGF – heparin-binding epidermal growth factor; HCNP – hippocampal cholinergic neurostimulating peptide; HGF – hepatocyte growth factor; IF – interferon; IGF – insulin-like growth factor; IGF-BP – IGF-binding protein; IL – interleukin; IP – IF-γ-induced protein; LIF – leukemia inhibitory factor; LPL – lipoprotein lipase; MCP – monocyte chemoattractant protein; MCSF – macrophage-colony-stimulating factor; MIF – macrophage migration inhibitory factor; MIP – macrophage inflammatory protein; MMP – matrix metalloproteinase; MW – molecular weight; NGAL – neutrophil gelatinase-associated lipocalin; NOV – nephroblastoma overexpressed protein; PAI – plasminogen activator inhibitor; PDGF – platelet-derived growth factor; PEDF – pigment-epithelium-derived factor; PG – prostaglandin; PTX – pentraxin-related protein; RANTES – regulated on activation, normal T cell expressed and secreted protein; RAS – renin-angiotensin system; RBP – retinol-binding protein; SA – serum amyloid; SDF – stromal-cell-derived factor; sIL6R – soluble IL6 receptor; sLepR – soluble leptin receptor; sTNFR – soluble TNF receptor; SSAO – semicarbazide-sensitive amine oxidase; TGF – transforming growth factor; TNF – tumor necrosis factor; VAP – vascular adhesion protein; VEGF – vascular endothelial growth factor; WISP – WNT1-inducible-signaling pathway protein.

Figure 2

Effects of adipocyte derived factors on insulin secretion. In the neighborhood of islets adipocytes secrete adiponectin. By activating the adiponectin receptor 1 (ADIPOR) on β-cells, adiponectin stimulates insulin secretion and β-cell survival. Leptin, which is also produced by preadipocytes, inhibits insulin secretion via the leptin receptor activation (LEP-R). Via the glucagon receptor (GCR) and β-adrenergic receptors (ADRB), respectively, glucagon and adrenaline stimulate lipolysis in the adipocytes, resulting in a release of fatty acids. Fatty acids acutely stimulate insulin secretion through fatty acid receptor 1 (FFAR1/GPR40). Fatty acids induce ER stress when taken up chronically at high concentrations. This is associated with increased β-cell death. Fatty acids also activate the toll-like receptor 4 (TLR4) which is involved in β-cell death and inflammation. TLR4-dependent stimulation of MCP-1 and IL-8 exerts chemotactic effects on monocytes. TLR4 stimulation of tissue macrophages activates the release of the cytotoxic cytokine IL-1β and induces β-cell death.