Changes in adipocytes and dendritic cells in lymph node containing adipose depots during and after many weeks of mild inflammation

Abstract

The time course and cellular basis for inflammation-induced hypertrophy of adipose tissue were investigated over 20 weeks in mature male rats. Mild inflammation was induced by subcutaneous injection of 20 microg lipopolysaccharide into one hind-leg three times/week for 4 or 8 weeks, followed by up to 12 weeks 'rest' without intervention. Mean volume and frequency of apoptosis (TUNEL assay) were measured in adipocytes isolated from sites defined by their anatomical relations to lymph nodes, plus numbers of CCL21-stimulated lymph node-derived and adipose tissue-derived dendritic cells. Experimental inflammation increased dendritic cells and adipocyte apoptosis in the locally stimulated popliteal depot and the lymphoid tissue-associated regions of the contralateral popliteal and mesentery and omentum. Responses declined slowly after inflammation ended, but all measurements from the locally stimulated popliteal depot, and the omentum, were still significantly different from controls after 12 weeks rest. The locally stimulated popliteal adipose tissue enlarged by 5% within 4 weeks and remained larger than the control. We conclude that prolonged inflammation induces permanent enlargement, greater adipocyte turnover and increased dendritic cell surveillance in the adjacent adipose tissue and the omentum. The experiment suggests a mechanism for selective hypertrophy of lymphoid tissue-associated adipose tissue in chronic stress and inflammatory disorders, including impaired lymph drainage, Crohn's disease and HIV-associated lipodystrophy, and a link between evolutionary fitness, sexual selection and aesthetically pleasing body symmetry. It would be useful for further study of molecular mechanisms in inflammation-induced local hypertrophy of adipose tissue and development of specific therapies that avoid interference with whole-body lipid metabolism.

Fig. 1

Time course of numbers of dendritic cells extracted from the adipose samples. Mean ± SE of numbers of CCL21-stimulated dendritic cells collected over 4 h from 50 mg adipose tissue. (A) Perinodal (large upright triangles), middle (right-pointing, middle-sized triangles) and remote (small inverted triangles) adipocytes from the popliteal adipose depots of the stimulated (solid symbols and lines) and unstimulated (open symbols and broken lines) legs. (B) Mesentery (circles) and omentum (squares), perinodal or milky spot-rich (closed symbols) and remote-from-lymphoid structure (open symbols). n = 8 × 3 cage-mate large male rats for controls, and 7 × 3 for other groups.

Fig. 2

Site-specific differences in adipocyte volume and time course of its changes. Mean ± SE of volume (nl) of perinodal (upright large triangles), middle (right-pointing, middle-sized triangles) and remote (small inverted triangles) adipocytes from the popliteal adipose depots of the unstimulated (A) and stimulated leg (B). n = 8 × 3 cage-mate rats for controls, and 7 × 3 for other groups. *Differences between homologous samples from stimulated and unstimulated legs significant at P < 0.05.

Fig. 3

Time course of changes in mass of the popliteal depots. Means ± SE of the gross mass (g) of the popliteal adipose depots from the stimulated (solid symbols and lines) and unstimulated (open symbols and broken lines) legs. n = 24 for controls, and 21 for other groups. Differences between popliteal depots from stimulated and unstimulated legs significant at: *P < 0.05; **P < 0.01; ***P < 0.001.

Fig. 4

Site-specific differences in adipocyte apoptosis and time course of its changes. Mean ± SE of the relative abundance (%) of TUNEL-positive apoptotic adipocytes isolated from perinodal (large upright triangles), middle (middle-sized right-pointing triangles) and remote (small inverted triangles) samples from the popliteal depots of the stimulated (solid symbols and lines) and unstimulated (open symbols and broken lines) legs, and from the perinodal mesenteric (circles) and omental milky spot-rich tissue (squares). (A) Within 6 h post mortem; (B) 24 h post mortem (data from popliteal depots only shown). n = 8 × 3 cage-mate rats for controls, and 7 × 3 for other groups.