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Treatment of obesity

a technology of lipid oxidation and obesity, applied in the field of obesity treatment, can solve the problems of leptin resistance, no consistent and effective weight loss, and limited anti-obesity drug trials

Inactive Publication Date: 2010-08-19
BAKER MEDICAL RES INST +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The patent text describes a method for inducing lipid oxidation in a mammal by administering a ligand that binds to the IL-6 receptor and signals via a gp130 / LIF receptor heterodimer. The technical effect of this method is the ability to induce lipid oxidation and treat conditions characterized by unwanted lipid accumulation. The patent also describes a specific ligand that can be used for this method."

Problems solved by technology

Although obesity is an individual clinical condition, some authorities view it as a serious and growing public health problem, particularly since excessive body weight has been linked to the onset of diseases such as cardiovascular diseases, insulin resistance, dyslipidemia, hypertension, diabetes mellitus type 2 and sleep apnea.
Disappointingly, none has resulted in consistent and effective weight loss, and to date, all anti-obesity drug trials have been limited by their high attrition rates and lack of long-term morbidity and mortality data (Padwal, R S, and Majumdar, S R (2007) Drug treatment for obesity: orlistat, sibutramine, and rimonbant, Lancet 369:71-77).
However, it soon became apparent that obesity, in which high circulating concentrations of leptin develop, resulted in leptin resistance whereby endogenous leptin was no longer effective (Van Heek, M et. al.
However, despite these major advanced in the understanding of the molecular processes as to how gp130 receptor ligands may enhance insulin sensitivity and act as “anti-obesogenic” agents, clinical trials have not been successful.
The first is that IL-6 is pro-inflammatory and while it has positive effects on energy balance and insulin sensitivity when administered acutely, it has negative effects on the progression of many diseases.
Secondly, CNTF failed in clinical trials because patients developed antibodies to Axokine®, the human recombinant variant of CNTF (Ettinger, M P, et. al.

Method used

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Examples

Experimental program
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Effect test

example 1

[0155]IC-7 was made in accordance with Kallen et. al. (1999) supra. More specifically IC-7 was developed by substituting the site III loop of IL-6 with the site III loop of CNTF (Kallen et. al., (1999) supra.). The site loop is situated on the C-terminal end of the protein and is the region which binds the either one gp130Rβ or the LIFRβ (FIG. 3).

example 2

IC-7 Stimulates Glucose Uptake in Soleus Muscle

[0156]The soleus muscle was dissected tendon to tendon from anaesthetised C57Bl / 6 mice and placed immediately into 2 mL of pre-gassed (95% O2, 5% CO2) Krebs-Henseleit buffer and incubated for 10 minutes in a 30° C. water bath with agitation. After 30 minutes of pre-incubation, this buffer was stimulated with insulin, cytokines or a co-treatment of both and incubated for a further 30 minutes. Muscles were then placed into 2 mL of Krebs-Henseleit buffer containing 3H-deoxyglucose, 14C-mannitol and the appropriate stimulus (insulin, cytokine or both) and incubated for 15 mins. Muscles were washed with saline, weighed and processed for determination of the uptake of labelled glucose.

[0157]The soleus muscles of C57Bl / 6 mice were assayed for the effect of insulin, IC-7 and co-treatment of insulin and IC-7 on glucose uptake. As expected, insulin led to 159% increase in skeletal muscle glucose uptake (FIG. 3). IC-7 (100 ng / mL) stimulation led t...

example 3

Acute Effects of IC-7 on Food Intake, Body Mass and Insulin Sensitivity In Vivo

[0159]The data in Example 2 indicates that IC-7 would be a more potent gp130 receptor ligand compared with CNTF. This is most significant because patients in the human trial for Axokine® only developed antibodies on high doses of the peptide (Ettinger et. al. (2003) supra). In previous studies using CNTF, it has been shown that a subcutaneous injection of 0.3 mg / kg was effective in activating AMPK and phosphorylating ACCβ, enhancing fat oxidation and increasing insulin action. Accordingly, these experiments are repeated with the addition of 3 doses of IC-7 (0.05, 0.1 and 0.3 mg / kg). Briefly, male C57 / Bl6 mice (4 weeks of age) mice are placed on a high fat diet for 12 weeks. After this time, conscious mice are injected with the ligands at the aforementioned doses and skeletal muscle and liver are harvested after 45 min. Samples are analysed for activation of AMPK, and phosphorylation of ACCβ, fat oxidation...

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Abstract

The present invention relates generally to a method of increasing lipid oxidation in a mammal and to agents useful for same. More particularly, the present invention relates to a method of increasing lipid oxidation in a mammal by administering a ligand which interacts with the IL-6 receptor and signals via interaction with a gp130 / LIF receptor heterodimer. In a related aspect, the present invention provides a method of increasing insulin sensitivity in a mammal. The method of present invention is useful, inter alia, in the treatment and / or prophylaxis of conditions characterised by unwanted lipid accumulation (such as obesity, obesity induced-metabolic disorders, type II diabetes, dyslipidemia, glucose intolerance, insulin resistance, obstructive sleep apnea, cardiovascular disease or non-alcoholic fatty liver disease) or inadequate insulin sensitivity.

Description

FIELD OF THE INVENTION[0001]The present invention relates generally to a method of increasing lipid oxidation in a mammal and to agents useful for same. More particularly, the present invention relates to a method of increasing lipid oxidation in a mammal by administering a ligand which interacts with the IL-6 receptor and signals via interaction with a gp130 / LIF receptor heterodimer. In a related aspect, the present invention provides a method of increasing insulin sensitivity in a mammal. The method of present invention is useful, inter alia, in the treatment and / or prophylaxis of conditions characterised by unwanted lipid accumulation (such as obesity, obesity induced-metabolic disorders, type II diabetes, dyslipidemia, glucose intolerance, insulin resistance, obstructive sleep apnea, cardiovascular disease or non-alcoholic fatty liver disease) or inadequate insulin sensitivity.BACKGROUND OF THE INVENTION[0002]Bibliographic details of the publications referred to by author in thi...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/20C07K14/54A61P3/10
CPCA61K38/00C07K14/475C07K14/48C07K2319/00C07K14/5412A61P3/00A61P3/04A61P3/08A61P3/10A61P5/50
Inventor FEBBRAIO, MARK ANTHONYROSE-JOHN, STEFAN
Owner BAKER MEDICAL RES INST