Insulin acts in the hypothalamus, decreasing food intake (FI) by the IR/PI3K/Akt pathway. This pathway is impaired in obese animals and endoplasmic reticulum (ER) stress and low-grade inflammation are possible mechanisms involved in this impairment. Here, we highlighted the amygdala as an important brain region for FI regulation in response to insulin. This regulation was dependent on PI3K/AKT pathway similar to the hypothalamus. Insulin was able to decrease neuropeptide Y (NPY) and increase oxytocin mRNA levels in the amygdala via PI3K, which may contribute to hypophagia. Additionally, obese rats did not reduce FI in response to insulin and AKT phosphorylation was decreased in the amygdala, suggesting insulin resistance. Insulin resistance was associated with ER stress and low-grade inflammation in this brain region. The inhibition of ER stress with PBA reverses insulin action/signaling, decreases NPY and increases oxytocin mRNA levels in the amygdala from obese rats, suggesting that ER stress is probably one of the mechanisms that induce insulin resistance in the amygdala.

IKK epsilon (IKK«) is induced by the activation of nuclear factor-kB (NF-kB). Whole-body IKK« knockout mice on a high-fat diet (HFD) were protected from insulin resistance and showed altered energy balance. We demonstrate that IKK« is expressed in neurons and is upregulated in the hypothalamus of obese mice, contributing to insulin and leptin resistance. Blocking IKK« in the hypothalamus of obese mice with CAYMAN10576 or small interfering RNA decreased NF-kB activation in this tissue, relieving the inflammatory environment. Inhibition of IKK« activity, but not TBK1, reduced IRS-1 Ser307 phosphorylation and insulin and leptin resistance by an improvement of the IR/IRS-1/Akt and JAK2/STAT3 pathways in the hypothalamus. These improvements were independent of body weight and food intake. Increased insulin and leptin action/signaling in the hypothalamus may contribute to a decrease in adiposity and hypophagia and an enhancement of energy expenditure accompanied by lower NPY and increased POMC mRNA levels. Improvement of hypothalamic insulin action decreases fasting glycemia, glycemia after pyruvate injection, and PEPCK protein expression in the liver of HFD-fed and db/db mice, suggesting a reduction in hepatic glucose production. We suggest that IKK« may be a key inflammatory mediator in the hypothalamus of obese mice, and its hypothalamic inhibition improves energy and glucose metabolism.

Young-Bum Kim 5 & patricia oliveira prada 1,2 ✉ A previous study demonstrated that a high-fat diet (HFD), administered for one-three-days, induces hypothalamic inflammation before obesity's established, and the long term affects leptin signaling/ action due to inflammation. We investigate whether exposure to particulate matter of a diameter of ≤2.5 μm (pM 2.5) in mice fed with a chow diet leads to similar metabolic effects caused by high-fat feeding. Compared to the filtered air group (FA), one-day-exposure-PM 2.5 did not affect adiposity. However, five-days-exposure-PM 2.5 increased hypothalamic microglia density, toll-like-receptor-4 (Tlr4), and the inhibitor-NF-kappa-B-kinase-epsilon (Ikbke) expression. Concurrently, fat mass, food intake (FI), and ucp1 expression in brown adipose tissue were also increased. Besides, decreased hypothalamic STAT3-phosphorylation and Pomc expression were found after twelve-weeksexposure-pM 2.5. These were accompanied by increased FI and lower energy expenditure (EE), leading to obesity, along with increased leptin and insulin levels and HOMA. Mechanistically, the deletion of Tlr4 or knockdown of the Ikbke gene in the hypothalamus was sufficient to reverse the metabolic outcomes of twelve-weeks-exposure-PM 2.5. These data demonstrated that short-term exposure-PM 2.5 increases hypothalamic inflammation, similar to a HFD. Long-term exposure-PM 2.5 is even worse, leading to leptin resistance, hyperphagia, and decreased EE. These effects are most likely due to chronic hypothalamic inflammation, which is regulated by Tlr4 and Ikbke signaling.

Thus, the present study highlights the deleterious role that the amygdalar PTP1B has on energy homeostasis in obesity states. The reduction of PTP1B in the CeA may be a strategy for the treatment of obesity, insulin resistance and anxiety disorders.

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