Adipose macrophages with the anti-inflammatory M2 phenotype protect against obesity-induced inflammation and insulin resistance. Heme oxygenase-1 (HO-1), which elicits antioxidant and anti-inflammatory activity, modulates macrophage phenotypes and thus is implicated in various inflammatory diseases. Here, we demonstrate that the HO-1 inducer, hemin, protects against obesity-induced adipose inflammation by inducing macrophages to switch to the M2 phenotype. HO-1 induction by hemin reduced the production of proinflammatory cytokines (TNF-αand IL-6) from cocultured adipocytes and macrophages by inhibiting the activation of inflammatory signaling molecules (JNK and NF-κB) in both cell types. Hemin enhanced transcript levels of M2 macrophage marker genes (IL-4, Mrc1, and Clec10a) in the cocultures, while reducing transcripts of M1 macrophage markers (CD274 and TNF-α). The protective effects of hemin on adipose inflammation and macrophage phenotype switching were confirmed in mice fed a high-fat diet, and these were associated with PPARγupregulation and STAT6 activation. These findings suggest that induction of HO-1 with hemin protects against obesity-induced adipose inflammation through M2 macrophage phenotype switching, which is induced by the PPARγand STAT6 pathway. HO-1 inducers such as hemin may be useful for preventing obesity-induced adipose inflammation.

Obesity-induced adipose inflammation is characterized by recruitment of macrophages to adipose tissue and release of inflammatory cytokines. 4-1BB, a costimulatory receptor, modulates inflammatory processes through interaction with its ligand 4-1BBL on immune cell surfaces. In this study, we examined whether a 4-1BB/4-1BBL interaction between adipocytes and macrophages participates in obesity-induced adipose inflammation. We found that 4-1BB was expressed on adipocytes and was upregulated by obesity-related factors, which also enhanced 4-1BBL expression on macrophages. 4-1BB and/or 4-1BBL agonists, respectively, activated inflammatory signaling molecules (MAPK/IκBαand MAPK/Akt) in adipocytes and macrophages and enhanced the release of inflammatory cytokines (MCP-1, TNF-α, and IL-6). Moreover, disruption of the 4-1BB/4-1BBL interaction decreased the release of inflammatory cytokines from contact cocultured adipocytes/macrophages. These findings indicate that 4-1BB/4-1BBL-mediated bidirectional signaling in adipocytes/macrophages promotes adipose inflammation. 4-1BB and 4-1BBL may be useful targets for protection against obesity-induced adipose inflammation.

Adiponectin, an adipokine derived from the adipose tissue, manifests anti-inflammatory effects in the metabolically active organs and is, therefore, beneficial in various metabolic diseases associated with inflammation. However, the role of adiponectin in alleviating the hypothalamic inflammation connected to the pathogenesis of obesity has not yet been clearly interrogated. Here, we identified that the systemic administration of adiponectin suppresses the activation of microglia and thereby reverses the hypothalamic inflammation during short-term exposure to a high-fat diet. Additionally, we show that adiponectin induces anti-inflammatory effects in the microglial cell line subjected to an exogenous treatment with a saturated free fatty acid. In conclusion, the current study suggests that adiponectin suppresses the saturated free fatty acid-triggered the hypothalamic inflammation by modulating the microglial activation and thus maintains energy homeostasis.

Visfatin is an adipokine that is secreted from adipose tissue, and it is involved in a variety of physiological processes. In particular, visfatin has been implicated in metabolic diseases, such as obesity and type 2 diabetes, which are directly linked to systemic inflammation. However, the potential impacts of visfatin on the hypothalamic control of energy homeostasis, which is involved in microglial inflammation, have not fully been investigated. In this study, we found that treatment with exogenous recombinant visfatin protein led to the activation of the inflammatory response in a microglial cell line. In addition, we observed that central administration of visfatin led to the activation of microglia in the hypothalamus. Finally, we found that visfatin reduced food intake and body weight through activating POMC neurons in association with microglia activation in mice. These findings indicate that elevation of central visfatin levels may be associated with homeostatic feeding behavior in response to metabolic shifts, such as increased adiposity following inflammatory processes in the hypothalamus.

The hypothalamic arcuate nucleus (Arc) is a central unit that controls the appetite through the integration of metabolic, hormonal, and neuronal afferent inputs. Agouti-related protein (AgRP), proopiomelanocortin (POMC), and dopaminergic neurons in the Arc differentially regulate feeding behaviors in response to hunger, satiety, and appetite, respectively. At the time of writing, the anatomical and electrophysiological characterization of these three neurons has not yet been intensively explored. Here, we interrogated the overall characterization of AgRP, POMC, and dopaminergic neurons using genetic mouse models, immunohistochemistry, and whole-cell patch recordings. We identified the distinct geographical location and intrinsic properties of each neuron in the Arc with the transgenic lines labelled with cell-specific reporter proteins. Moreover, AgRP, POMC, and dopaminergic neurons had different firing activities to ghrelin and leptin treatments. Ghrelin led to the increased firing rate of dopaminergic and AgRP neurons, and the decreased firing rate of POMC. In sharp contrast, leptin resulted in the decreased firing rate of AgRP neurons and the increased firing rate of POMC neurons, while it did not change the firing rate of dopaminergic neurons in Arc. These findings demonstrate the anatomical and physiological uniqueness of three hypothalamic Arc neurons to appetite control.

Beta-aminoisobutyric acid (BAIBA), a natural thymine catabolite, is involved in the beneficial effects of exercise on metabolic disorders. In particular, it has been reported to reverse the inflammatory processes observed in the peripheral organs of animal models of obesity. Therefore, this study aimed to investigate whether BAIBA improves hypothalamic inflammation, which is also tightly coupled with the development of obesity. We observed that treatment with BAIBA effectively reversed palmitic acid-induced hypothalamic inflammation and microglial activation in vivo. Consistent with these findings, we confirmed that BAIBA reversed body weight gain and increased adiposity observed in mice fed with a high-fat diet. Collectively, the current findings evidence the beneficial impacts of BAIBA on the imbalance of energy metabolism linked to hypothalamic inflammation.