Tag Archives: Obesity.

Disruption of Lipid Uptake in Astroglia Exacerbates Diet-Induced Obesity

Neuronal circuits in the brain help to control feeding behavior and systemic metabolism in response to afferent nutrient and hormonal signals. Although astrocytes have historically been assumed to have little relevance for such neuroendocrine control, we investigated whether lipid uptake via lipoprotein lipase (LPL) in astrocytes is required to centrally regulate energy homeostasis. Ex vivo studies with hypothalamus-derived astrocytes showed that LPL expression is upregulated by oleic acid, whereas it is decreased in response to palmitic acid or triglycerides. Likewise, astrocytic LPL deletion reduced the accumulation of lipid droplets in those glial cells. Consecutive in vivo studies showed that postnatal ablation of LPL in glial fibrillary acidic protein–expressing astrocytes induced exaggerated body weight gain and glucose intolerance in mice exposed to a high-fat diet. Intriguingly, astrocytic LPL deficiency also triggered increased ceramide content in the hypothalamus, which may contribute to hypothalamic insulin resistance. We conclude that hypothalamic LPL functions in astrocytes to ensure appropriately balanced nutrient sensing, ceramide distribution, body weight regulation, and glucose metabolism.

Diabetes Journal current issue





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Hypothalamic Ventromedial Lin28a Enhances Glucose Metabolism in Diet-Induced Obesity

The Lin28a/Let-7 axis has been studied in peripheral tissues for its role in metabolism regulation. However, its central function remains unclear. Here we found that Lin28a is highly expressed in the hypothalamus compared with peripheral tissues. Its expression is positively correlated with positive energy balance, suggesting a potential central role for Lin28a in metabolism regulation. Thus, we targeted the hypothalamic ventromedial nucleus (VMH) to selectively overexpress (Lin28aKIVMH) or downregulate (Lin28aKDVMH) Lin28a expression in mice. With mice on a standard chow diet, body weight and glucose homeostasis were not affected in Lin28aKIVMH or Lin28aKDVMH mice. On a high-fat diet, although no differences in body weight and composition were observed, Lin28aKIVMH mice showed improved glucose tolerance and insulin sensitivity compared with controls. Conversely, Lin28aKDVMH mice displayed glucose intolerance and insulin resistance. Changes in VMH AKT activation of diet-induced obese Lin28aKIVMH or Lin28aKDVMH mice were not associated with alterations in Let-7 levels or insulin receptor activation. Rather, we observed altered expression of TANK-binding kinase-1 (TBK-1), which was found to be a direct Lin28a target mRNA. VMH-specific inhibition of TBK-1 in mice with diet-induced obesity impaired glucose metabolism and AKT activation. Altogether, our data show a TBK-1–dependent role for central Lin28a in glucose homeostasis.

Diabetes Journal current issue





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Single-Molecule Combinatorial Therapeutics for Treating Obesity and Diabetes

Diabetes Journal current issue





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Dietary Sugar and Body Weight: Have We Reached a Crisis in the Epidemic of Obesity and Diabetes?: Health Be Damned! Pour on the Sugar

George A. Bray
Apr 1, 2014; 37:950-956
Current Concepts of Type 2 Diabetes Prevention
: Most-Read Full-Text Articles





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Fat-Specific Sirt6 Ablation Sensitizes Mice to High-Fat Diet-Induced Obesity and Insulin Resistance by Inhibiting Lipolysis

Sirt6 is an NAD+-dependent deacetylase that is involved in the control of energy metabolism. However, the tissue-specific function of Sirt6 in the adipose tissue remains unknown. In this study, we showed that fat-specific Sirt6 knockout (FKO) sensitized mice to high-fat diet–induced obesity, which was attributed to adipocyte hypertrophy rather than adipocyte hyperplasia. The adipocyte hypertrophy in FKO mice likely resulted from compromised lipolytic activity as an outcome of decreased expression of adipose triglyceride lipase (ATGL), a key lipolytic enzyme. The suppression of ATGL in FKO mice was accounted for by the increased phosphorylation and acetylation of FoxO1, which compromises the transcriptional activity of this positive regulator of ATGL. Fat-specific Sirt6 KO also increased inflammation in the adipose tissue, which may have contributed to insulin resistance in high-fat diet–fed FKO mice. We also observed that in obese patients, the expression of Sirt6 expression is reduced, which is associated with a reduction of ATGL expression. Our results suggest Sirt6 as an attractive therapeutic target for treating obesity and obesity-related metabolic disorders.

Diabetes Journal current issue





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Deletion of CD1d in Adipocytes Aggravates Adipose Tissue Inflammation and Insulin Resistance in Obesity

Adipose tissue inflammation is an important factor in obesity that promotes insulin resistance. Among various cell types in adipose tissue, immune cells actively regulate inflammatory responses and affect whole-body energy metabolism. In particular, invariant natural killer T (iNKT) cells contribute to mitigating dysregulation of systemic energy homeostasis by counteracting obesity-induced inflammation in adipose tissue. However, the molecular mechanisms by which adipose iNKT cells become activated and mediate anti-inflammatory roles in obese adipose tissue have not been thoroughly understood yet. In the current study, we demonstrate that adipocyte CD1d plays a key role in the stimulation of adipose iNKT cells, leading to anti-inflammatory responses in high-fat diet (HFD)–fed mice. Accordingly, adipocyte-specific CD1d-knockout (CD1dADKO) mice showed reduced numbers of iNKT cells in adipose tissues and decreased responses to α-galactosylceramide–induced iNKT cell activation. Additionally, HFD-fed CD1dADKO mice revealed reduced interleukin-4 expression in adipose iNKT cells and aggravated adipose tissue inflammation and insulin resistance. Collectively, these data suggest that adipocytes could selectively stimulate adipose iNKT cells to mediate anti-inflammatory responses and attenuate excess proinflammatory responses in obese adipose tissue.

Diabetes Journal current issue





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Microglial Proliferation in Obesity: When, Where, Why, and What Does It Mean?

Diabetes Journal current issue





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Adipocyte Glucocorticoid Receptor Deficiency Attenuates Aging- and HFD-Induced Obesity and Impairs the Feeding-Fasting Transition

Glucocorticoids (GCs) are important regulators of systemic energy metabolism, and aberrant GC action is linked to metabolic dysfunctions. Yet, the extent to which normal and pathophysiological energy metabolism depend on the GC receptor (GR) in adipocytes remains unclear. Here, we demonstrate that adipocyte GR deficiency in mice significantly impacts systemic metabolism in different energetic states. Plasma metabolomics and biochemical analyses revealed a marked global effect of GR deficiency on systemic metabolite abundance and, thus, substrate partitioning in fed and fasted states. This correlated with a decreased lipolytic capacity of GR-deficient adipocytes under postabsorptive and fasting conditions, resulting from impaired signal transduction from β-adrenergic receptors to adenylate cyclase. Upon prolonged fasting, the impaired lipolytic response resulted in abnormal substrate utilization and lean mass wasting. Conversely, GR deficiency attenuated aging-/diet-associated obesity, adipocyte hypertrophy, and liver steatosis. Systemic glucose tolerance was improved in obese GR-deficient mice, which was associated with increased insulin signaling in muscle and adipose tissue. We conclude that the GR in adipocytes exerts central but diverging roles in the regulation of metabolic homeostasis depending on the energetic state. The adipocyte GR is indispensable for the feeding-fasting transition but also promotes adiposity and associated metabolic disorders in fat-fed and aged mice.

Diabetes Journal current issue





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Getting a “GRiP” on Hypothalamic Endoplasmic Reticulum Stress to Combat Obesity

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Targeting CITED2 for Angiogenesis in Obesity and Insulin Resistance

Diabetes Journal current issue





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