| 1. |
- López, Miguel, et al.
(författare)
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Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance
- 2010
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Ingår i: Nature Medicine. - : Nature Publishing Group. - 1078-8956 .- 1546-170X. ; 16:9, s. 1001-1008
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Tidskriftsartikel (refereegranskat)abstract
- Thyroid hormones have widespread cellular effects; however it is unclear whether their effects on the central nervous system (CNS) contribute to global energy balance. Here we demonstrate that either whole-body hyperthyroidism or central administration of triiodothyronine (T3) decreases the activity of hypothalamic AMP-activated protein kinase (AMPK), increases sympathetic nervous system (SNS) activity and upregulates thermogenic markers in brown adipose tissue (BAT). Inhibition of the lipogenic pathway in the ventromedial nucleus of the hypothalamus (VMH) prevents CNS-mediated activation of BAT by thyroid hormone and reverses the weight loss associated with hyperthyroidism. Similarly, inhibition of thyroid hormone receptors in the VMH reverses the weight loss associated with hyperthyroidism. This regulatory mechanism depends on AMPK inactivation, as genetic inhibition of this enzyme in the VMH of euthyroid rats induces feeding-independent weight loss and increases expression of thermogenic markers in BAT. These effects are reversed by pharmacological blockade of the SNS. Thus, thyroid hormone-induced modulation of AMPK activity and lipid metabolism in the hypothalamus is a major regulator of whole-body energy homeostasis.
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| 2. |
- Shrestha, Neha, et al.
(författare)
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The stimulation of GLP-1 secretion and delivery of GLP-1 agonists &ITvia&IT nanostructured lipid carriers
- 2018
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Ingår i: Nanoscale. - : Royal Society of Chemistry (RSC). - 2040-3364 .- 2040-3372. ; 10:2, s. 603-613
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Tidskriftsartikel (refereegranskat)abstract
- Nanoparticulate based drug delivery systems have been extensively studied to efficiently encapsulate and deliver peptides orally. However, most of the existing data mainly focus on the nanoparticles as a drug carrier, but the ability of nanoparticles having a biological effect has not been exploited. Herein, we hypothesize that nanostructured lipid carriers (NLCs) could activate the endogenous glucagon-like peptide-1 (GLP-1) secretion and also act as oral delivery systems for GLP-1 analogs (exenatide and liraglutide). NLCs effectively encapsulated the peptides, the majority of which were only released under the intestinal conditions. NLCs, with and without peptide encapsulation, showed effective induction of GLP-1 secretion in vitro from the enteroendocrinal L-cells (GLUTag). NLCs also showed a 2.9-fold increase in the permeability of exenatide across the intestinal cell monolayer. The intestinal administration of the exenatide and liraglutide loaded NLCs did not demonstrate any glucose lowering effect on normal mice. Further, ex vivo studies depicted that the NLCs mainly adhered to the mucus layer. In conclusion, this study demonstrates that NLCs need further optimization to overcome the mucosal barrier in the intestine; nonetheless, this study also presents a promising strategy to use a dual-action drug delivery nanosystem which synergizes its own biological effect and that of the encapsulated drug molecule.
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| 3. |
- Tovar, Sulay, et al.
(författare)
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Central administration of resistin promotes short-term satiety in rats.
- 2005
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Ingår i: European journal of endocrinology / European Federation of Endocrine Societies. - : Oxford University Press (OUP). - 0804-4643. ; 153:3
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Several hormones expressed in white adipose tissue influence food intake at the central level. We sought to determine whether resistin, a circulating adipose-derived hormone in rodents, has actions on the hypothalamus by determining the effects of central resistin injection on food intake and on hypothalamic Fos protein expression. DESIGN: As resistin expression in adipose tissue is influenced by altered nutritional status, we studied the effect of central resistin in both fed and pre-fasted rats. RESULTS: In fasted rats, central injection of resistin decreased food intake acutely and increased the number of cells that express Fos protein in the arcuate nucleus but not in any other hypothalamic structure. The effect on food intake was dose-dependent and did not result in the formation of a conditioned taste aversion. CONCLUSIONS: Taken together, these results provide the first evidence documenting a central action of resistin, which could be involved in a feedback loop targeting the hypothalamus. On the other hand, since we observed resistin mRNA in the arcuate and ventromedial nuclei of the hypothalamus, it is also possible that brain-derived resistin serves as a neuropeptide involved in the regulation of energy homeostasis. However, since resistin-induced satiety was modest and transient, as central administration for several days did not affect body weight, the physiological relevance and therapeutic potential of the observed principal phenomenon may be limited.
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