Preventing leptin resistance by blocking angiotensin II AT1 receptors in diet-induced obese rats
Helge Müller-Fielitz1, Margot Lau, Cathleen Geißler
1Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Lübeck, Germany.
Background And Purpose:
AT1 receptor blockers (ARBs) represent an approach for treating metabolic syndrome due to their potency in reducing hypertension, body weight and onset of type 2 diabetes. The mechanism underlying ARB-induced weight loss is still unclear.
Experimental Approach:
Leptin resistance tests (LRTs) in diet-induced obese or lean rats were conducted to determine whether telmisartan (8 mg·kg(-1) ·day(-1) , 14 days) enhances leptin sensitivity. Phosphorylation of signal transducer and activator of transcription 3 (pSTAT3) staining was performed in hypothalami to determine leptin transport across the blood-brain barrier.
Key Results:
Telmisartin reduced weight gain, food intake and plasma leptin but blood pressure remained unchanged. The 24 h profiles of plasma leptin after saline injections were similar in controls and telmisartan-treated rats, but after leptin injections were higher in controls and slightly lower in telmisartan-treated animals. After telmisartan, energy intake during LRT was lower in leptin- than in saline-pretreated rats, but remained unchanged in controls, irrespectively of whether rats received saline or leptin. Leptin minimized the gain in body weight during LRT in telmisartan-treated rats as compared with saline-treated animals. pSTAT3 staining was reduced in cafeteria diet-fed rats as compared with chow-fed rats but this was normalized by telmisartan. Telmisartin reduced hypothalamic mRNA levels of the orexigenic peptides melanin-concentrating hormone and prepro-orexin.
Conclusions And Implications:
Rats fed a cafeteria diet develop leptin resistance after 2 weeks. Leptin sensitivity was preserved by telmisartan treatment even in rats fed a cafeteria diet. This pleiotropic effect is not related to the hypotensive action of telmisartan.
Insights
Telmisartan treatment preserves leptin sensitivity in rats with diet-induced obesity, reducing weight gain and food intake. This effect is independent of blood pressure changes, suggesting a pleiotropic mechanism for Angiotensin II Receptor Blockers (ARBs).
Area of Science:
- Metabolic Syndrome Research
- Pharmacology
- Neuroendocrinology
Background:
- Angiotensin II Receptor Blockers (ARBs) show potential in managing metabolic syndrome by reducing hypertension, weight gain, and type 2 diabetes onset.
- The precise mechanisms behind ARB-induced weight loss, particularly concerning leptin signaling, remain incompletely understood.
Purpose of the Study:
- To investigate whether telmisartan enhances leptin sensitivity in diet-induced obese rats.
- To explore the impact of telmisartan on leptin transport across the blood-brain barrier and hypothalamic gene expression.
Main Methods:
- Leptin resistance tests (LRTs) were performed on rats with diet-induced obesity or lean controls.
- Telmisartan (8 mg·kg⁻¹·day⁻¹) was administered for 14 days.
- Hypothalamic pSTAT3 staining and mRNA levels of orexigenic peptides were analyzed.
Main Results:
- Telmisartan reduced weight gain, food intake, and plasma leptin levels without altering blood pressure.
- Leptin sensitivity was preserved in telmisartan-treated rats, evidenced by reduced energy intake during LRT and minimized weight gain.
- Telmisartan normalized reduced pSTAT3 staining in the hypothalamus of obese rats and decreased hypothalamic mRNA levels of melanin-concentrating hormone and prepro-orexin.
Conclusions:
- Diet-induced obesity in rats leads to leptin resistance within two weeks.
- Telmisartan treatment maintained leptin sensitivity even in rats on a cafeteria diet.
- The observed beneficial effects of telmisartan are likely pleiotropic and not solely attributable to its antihypertensive properties.
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