Partial Leptin Reduction as an Insulin Sensitization and Weight Loss Strategy

Abstract

The physiological role of leptin is thought to be a driving force to reduce food intake and increase energy expenditure. However, leptin therapies in the clinic have failed to effectively treat obesity, predominantly due to a phenomenon referred to as leptin resistance. The mechanisms linking obesity and the associated leptin resistance remain largely unclear. With various mouse models and a leptin neutralizing antibody, we demonstrated that hyperleptinemia is a driving force for metabolic disorders. A partial reduction of plasma leptin levels in the context of obesity restores hypothalamic leptin sensitivity and effectively reduces weight gain and enhances insulin sensitivity. These results highlight that a partial reduction in plasma leptin levels leads to improved leptin sensitivity, while pointing to a new avenue for therapeutic interventions in the treatment of obesity and its associated comorbidities.

Lmo4‐resistin signaling contributes to adipose tissue‐liver crosstalk upon weight cycling

“…Increasing circulating leptin level and leptin mRNA level in adipose tissue are also affected by weight cycling (Figure A‐C). Increased serum leptin level have been demonstrated to activate p‐STAT3 levels in immunoreactive cells in certain neurons of obese mice; while partial reducing circulating leptin level by a leptin neutralizing antibody in obese mice protects mouse from diet‐induced obesity by restores leptin sensitivity in hypothalamic neurons . Increased circulating Il‐6 level may also contribute to hepatic inflammation .…”

“…Increased serum leptin level have been demonstrated to activate p-STAT3 levels in immunoreactive cells in certain neurons of obese mice 52 ; while partial reducing circulating leptin level by a leptin neutralizing antibody in obese mice protects mouse from diet-induced obesity by restores leptin sensitivity in hypothalamic neurons. 53 Increased circulating Il-6 level may also contribute to hepatic inflammation. 54 However, in the present study, serum level of Il-6 was not further upregulated in the HF-LF cycled mice compared to that of HF mice ( Figure 6C), which was consistent with less inflamed adipose tissue and more inflamed liver of HF-LF cycled mice ( Figures 3D and 4D), since both tissues can secret Il-6 and affect its circulating level.…”

Circadian rhythms and obesity: Timekeeping governs lipid metabolism

“…64 The homeostasis of leptin plays an important role in food intake, energy expenditures, lipid metabolism, insulin sensitization, and food-anticipatory rhythms. [65][66][67][68] However, leptin resistance, a hallmark of obesity in humans, is involved in circadian dysfunction-induced obesity and metabolic syndromes. 63 Additionally, leptin regulates the synthesis of neuropeptides that control food intake and energy homeostasis by the leptin receptor.…”

Alliin, An Allium sativum Nutraceutical, Reduces Metaflammation Markers in DIO Mice

“…Additionally, its satiety function in the hypothalamus is attenuated, because of the incorrect ability of leptin to suppress appetite, named leptin resistance, promoting energy intake by the subject [61]. The fact that alliin significantly decreased leptin levels explains the improvement of satiety and implies an improvement in lipid metabolism by diminishing adipocyte metabolic stress, which involves the functions described for leptin [62,63]. In addition, because adiponectin is considered a functional leptin antagonist, subsequently, the reduction of leptin suggests a possible improvement in adiponectin's activity: insulin sensitivity, adequate adipogenesis, and amelioration of hyperlipidemia showing lipid homeostasis [59].…”