Deletion of Suppressor of Cytokine Signaling 3 from Forebrain Neurons Delays Infertility and Onset of Hypothalamic Leptin Resistance in Response to a High Caloric Diet

Abstract

Obesity is commonly associated with infertility in humans and other animals. Treatments for human infertility show a decreased success rate with increasing body mass index. A hallmark of obesity is an increase in circulating leptin levels; despite this, the brain responds as if there were low levels of leptin, leading to increased appetite and suppressed fertility. Here we show that leptin resistant infertility is caused in part by the leptin signaling molecule SOCS3. Deletion of SOCS3 from brain neurons delays the onset of diet-induced infertility.

Depletion of the gut microbiota differentially affects the impact of whey protein on high‐fat diet‐induced obesity and intestinal permeability

“…It acts by binding leptin receptor and inhibiting downstream the signaling cascade. Rodents with Socs3 deletion in proopiomelanocortin (POMC) neurons are resistant to diet-induced obesity and have lower levels of circulating leptin (Bian et al, 2013;McEwen et al, 2016;Mori et al, 2004). On the other hand, Socs3 upregulation promotes hypothalamic leptin resistance (Reed et al, 2010).…”

Multiple Leptin Signalling Pathways in the Control of Metabolism and Fertility: A Means to Different Ends?

“…Other signalling pathways are therefore involved in mediating leptin's effects on the network of afferent inputs to the gonadotrophin-releasing hormone neurons governing fertility (such as AgRP/NPY neurons). Nevertheless, it remains very common to validate animal models of 'leptin resistance' simply by showing impaired STAT3 signalling, even when fertility outcomes are being considered (e.g., [23,34]).…”

“…To investigate whether upregulated SOCS3 also plays a role in high calorie diet (HCD)induced infertility, our group generated mice exhibiting SOCS3 knockout from all forebrain neurons and monitored reproductive and metabolic parameters in response to HCD feeding. Interestingly, male and female neuron-specific SOCS3 knockout mice showed different levels of protection from leptin resistance in response to HCD-feeding, whereby the male knockout vs. control mice were almost entirely protected from HCD-induced obesity, whereas the female knockout vs. control mice exhibited very limited protection from HCD-induced obesity [23]. Furthermore, while HCD-fed male mice remained completely fertile, the female control mice developed HCD-induced infertility and this was prevented for over a month by SOCS3 knockout.…”

“…However, while obesity-related infertility is becoming increasingly common [21], it is nevertheless possible to exhibit resistance to leptin's 'anti-obesity' effects while remaining fertile [22]. For example, the fact that central leptin resistance leads to dysregulation of feeding much more quickly than dysregulation of fertility [23] presumably allows for excessive late summer and autumn feeding and fat accumulation without disruption of fertility in seasonal animals that mate at this time. Improving our understanding of how the development of leptin resistance differentially impacts metabolic and reproductive function is therefore an active area of research.…”

Macronutrient intake, insulin secretion, oxidative stress & inflammation

“…Thus, it is clear that the cumulative effect of such meals consumed habitually is likely to result in insulin resistance and caloric overload 25 . In addition, since SOCS-3 interferes with leptin signalling, such meals could potentially result in lack of satiety and an increase in caloric intake 26 27 . Progressive weight gain with insulin resistance would lead to hypertension and hypertriglyceridaemia and thus to metabolic syndrome.…”