TLR4 in POMC neurons regulates thermogenesis in a sex-dependent manner.

The rising prevalence of obesity has become a worldwide health concern. Obesity usually occurs when there is an imbalance between energy intake and energy expenditure. However, energy expenditure consists of several components, including metabolism, physical activity, and thermogenesis. Toll-like receptor 4 (TLR4) is a transmembrane pattern recognition receptor, and it is abundantly expressed in the brain. Here, we showed that pro-opiomelanocortin (POMC)-specific deficiency of TLR4 directly modulates brown adipose tissue thermogenesis and lipid homeostasis in a sex-dependent manner. Deleting TLR4 in POMC neurons is sufficient to increase energy expenditure and thermogenesis resulting in reduced body weight in male mice. POMC neuron is a subpopulation of tyrosine hydroxylase neurons and projects into brown adipose tissue, which regulates the activity of sympathetic nervous system and contributes to thermogenesis in POMC-TLR4-KO male mice. By contrast, deleting TLR4 in POMC neurons decreases energy expenditure and increases body weight in female mice, which affects lipolysis of white adipose tissue (WAT). Mechanistically, TLR4 KO decreases the expression of the adipose triglyceride lipase and lipolytic enzyme hormone-sensitive lipase in WAT in female mice. Furthermore, the function of immune-related signaling pathway in WAT is inhibited because of obesity, which exacerbates the development of obesity reversely. Together, these results demonstrate that TLR4 in POMC neurons regulates thermogenesis and lipid balance in a sex-dependent manner.

Corticotropin-releasing factor receptor type 2 in the midbrain critically contributes to the hedonic feeding behavior of mice under heat stress.

Heat stress is an important factor that affects food intake. Previous studies have proven that heat stress can regulate feeding behavior through a homeostasis pathway and decrease appetite in animals and humans. However, the relationship between heat stress and midbrain reward regulation has not been reported. Corticotropin-releasing factor receptor type 2 (CRFR2) is the receptor of corticotropin-releasing factor (CRF), which is the key hypothalamic pituitary adrenal axis (HPA axis) regulating the stress response. In our study, the effects of heat stress on hedonic feeding behavior were investigated. The results showed that heat stress can affect hedonic feeding behavior and decrease high-fat diet (HFD) intake. Furthermore, the mRNA expression of tyrosine hydroxylase in the VTA decreased under heat stress compared with that at 25 °C. Meanwhile, intraventricular injection of a CRFR2 antagonist reversed the decrease in HFD intake and conditional place preference (CPP) caused by heat stress. In conclusion, CRFR2 in the midbrain plays an important role in the decrease in hedonic feeding behavior caused by heat stress.

Food reward depends on TLR4 activation in dopaminergic neurons.

The rising prevalence of obesity and being overweight is a worldwide health concern. Food reward dysregulation is the basic factor for the development of obesity. Dopamine (DA) neurons in the ventral tegmental area (VTA) play a vital role in food reward. Toll-like receptor 4 (TLR4) is a transmembrane pattern recognition receptor that can be activated by saturated fatty acids. Here, we show that the deletion of TLR4 specifically in DA neurons increases body weight, increases food intake, and decreases food reward. Conditional deletion of TLR4 also decreased the activity of DA neurons while suppressing the expression of tyrosine hydroxylase (TH) in the VTA, which regulates the concentration of DA in the nucleus accumbens (NAc) to affect food reward. Meanwhile, AAV-Cre-GFP mediated VTA-specific TLR4-deficient mice recapitulates food reward of DAT-TLR4-KO mice. Food reward could be rescued by re-expressing TLR4 in VTA DA neurons. Moreover, effects of intra-VTA infusion of lauric acid (a saturated fatty acid with 12 carbon) on food reward were abolished in mice lacking TLR4 in DA neurons. Our study demonstrates the critical role of TLR4 signaling in regulating the activity of VTA DA neurons and the normal function of the mesolimbic DA system that may contribute to food reward.

Diet containing stearic acid increased food intake in mice by reducing serum leptin compared with oleic acid.

In today's society, obesity is becoming increasingly serious, and controlling food intake and maintaining weight balance have become increasingly important. Here, we found that a stearic acid diet can increase food intake without causing obesity in mice compared with an oleic acid diet. Stearic acid increases food intake in mice by reducing serum leptin and increasing NPY neuronal excitability through the JAK2/STAT3 pathway. The impaired anorexic effect of leptin is probably due to repressive cholesterol-oxysterol-LXR-α/SREBP-1c-mediated leptin expression in mouse iWAT. At the same time, we found that stearic acid was not only poorly absorbed by itself in the small intestine but also reduced the entire absorption system of the small intestine. In conclusion, we have proven that a stearic acid diet can increase food intake in mice and avoid obesity, but whether a stearic acid diet could cause adverse reactions in the body remains to be studied.

TLR4 in Tph2 neurons modulates anxiety-related behaviors in a sex-dependent manner.

TLR4 belongs to the TLR receptor family and can induce a proinflammatory response to invading pathogens. Recent studies have identified that TLR4 is associated with major anxiety disorder. Tph2 is a rate-limiting enzyme for 5-HT biosynthesis that is expressed at high levels in the DRN, which includes the main 5-HT projection to the hippocampus and prefrontal cortex and regulates anxiety disorder. Here, we show that TLR4 expressed in Tph2 neurons in the DRN can modulate anxiety-like behaviors in a sex-dependent manner. Deletion of TLR4 in Tph2 neurons decreases anxiety-like behaviors in male but not in female mice. Meanwhile, a similar phenotype was found by selectively ablating TLR4 in the DRN of adult male but not female mice using AAV-Cre-GFP virus. Inhibition of TLR4 in DRN by infusion of LPS-RS via intra-Aq is sufficient to reverse anxiety-like behavior induced by chronic immobilization stress (CIS). The underlying mechanisms seem to involve alterations in the activity of Tph2 neurons and key components of 5-HT transmission, including synthesis, reuptake, and transmission. Our results suggest that TLR4 in Tph2 neurons is a key modulator in anxiety-like behaviors and the 5-HT system in the brain between different sexes.