Adipocyte subpopulations mediate lipolysis and obesity-induced insulin resistance.

Studies in humans and mice have determined that distinct subpopulations of adipocytes reside even within individual adipose tissue depots. Previously, our lab defined three white adipocyte subpopulations with stable and unique gene expression profiles, which were termed type 1, 2, and 3 adipocytes, respectively. Our previous studies demonstrated that type 2 adipocytes were highly responsive to the inflammatory cytokine, tumor necrosis factor alpha (TNFα). This study extends these findings to investigate the role of type 2 adipocytes in obesity. We found that treatment with TNFα increased lipolysis specifically in type 2 adipocytes, at least in part, through the reduction of fat-specific protein 27 (FSP27) expression. To assess the physiological role of lipolysis from this adipocyte subpopulation, a type2Ad-hFSP27tg mouse model was generated by overexpressing human FSP27 specifically in type 2 adipocytes. Glucose and insulin tolerance test analysis showed that male type2Ad-hFSP27tg mice on 60% high-fat diet exhibited improved glucose tolerance and insulin sensitivity, with no change in body weight compared to controls. These metabolic changes may, at least in part, be explained by the reduced lipolysis rate in the visceral fat of type2Ad-hFSP27tg mice. Although FSP27 overexpression in primary type 2 adipocytes was sufficient to acutely reduce TNFα-induced apoptosis in vitro, it failed to reduce macrophage infiltration in obesity in vivo. Taken together, these results strongly suggest that type 2 adipocytes contribute to the regulation of lipolysis and could serve as a potential therapeutic target for obesity-associated insulin resistance.

Neuroprotective Effects of Shogaol in Metals (Al, As and Pb) and High-fat diet-induced Neuroinflammation and Behavior in Mice.

BACKGROUND: Increased exposure of humans to toxic metals and high-fat diet (HFD) consumption severely damages brain health. Natural plant extracts have shown huge potential to treat multiple human diseases. OBJECTIVE: The present study was designed to evaluate the protective effects of Shogaol (an active component of ginger) in neuroinflammation and behavioral paradigms in mice treated with metals and HFD. METHODS: 8-11 weeks old male mice model was developed by giving a combination of metals, i.e., Arsenic (As), Lead (Pb) and Aluminum (Al), 25mg/kg each mixed in drinking water with laboratory prepared HFD (40% fat) for a total duration of 72 days. Shogaol treated groups received two doses (2mg/kg & 12mg/kg) of Shogaol along with metals and HFD. The biochemical parameters, including body weights, blood glucose, and kidney and liver functions, were assessed along with the integrity of the blood-brain barrier (BBB). The expression analysis of neuroinflammatory genes (TNF-α, IL-1ß & GFAP) was performed using q-PCR in the hippocampus and cortex. The exploratory and anxiety-like behavior was assessed using an open field test, and depressive behavior was assessed through the forced swim test, while learning and memory were assessed using the Morris water maze test and y-maze test. RESULTS: Shogaol (2mg/kg & 12mg/kg) treatment improved metabolic profile and reduced expression of neuroinflammatory genes in the cortex and the hippocampus. Shogaol treatment improved BBB integrity. Results of the behavioral analysis showed that Shogaol treatment (2mg/kg & 12mg/kg) rescued behavioral impairment and improved anxiety and depression. CONCLUSION: Shogaol treatment showed strong therapeutic potential in metals & HFD induced neuroinflammation and improved cognitive functions; thus, can be considered a potential drug candidate in the future.

Adipocyte Subpopulations Mediate Growth Hormone-induced Lipolysis and Glucose Tolerance in Male Mice.

In adipose tissue, growth hormone (GH) stimulates lipolysis, leading to an increase in plasma free fatty acid levels and a reduction in insulin sensitivity. In our previous studies, we have found that GH increases lipolysis by reducing peroxisome proliferator-activated receptor γ (PPARγ) transcription activity, leading to a reduction of tat-specific protein 27 (FSP27, also known as CIDEC) expression. In previous studies, our laboratory uncovered 3 developmentally distinct subpopulations of white adipocytes. In this manuscript, we show that one of the subpopulations, termed type 2 adipocytes, has increased GH-induced signaling and lipolysis compared to other adipocyte subtypes. To assess the physiological role of GH-mediated lipolysis mediated by this adipocyte subpopulation, we specifically expressed human FSP27 (hFSP27) transgene in type 2 adipocytes (type2Ad-hFSP27tg mice). Systemically, male type2Ad-hFSP27tg mice displayed reduced serum glycerol release and nonesterified fatty acids levels after acute GH treatment, and improvement in acute, but not chronic, GH-induced glucose intolerance. Furthermore, we demonstrate that type2Ad-hFSP27tg mice displayed improved hepatic insulin signaling. Taken together, these results indicate that this adipocyte subpopulation is a critical regulator of the GH-mediated lipolytic and metabolic response. Thus, further investigation of adipocyte subpopulations may provide novel treatment strategies to regulate GH-induced glucose intolerance in patients with growth and metabolic disorders.