RESEARCH HIGHLIGHTS
M E TA B O L I S M
Sugar on the brain Glucose homeostasis is not only regulated by the liver and pancreas; recent studies have shown that the hypothalamus also has a role in this process. However, whether changes in the hypothalamic regulation of glucose homeostasis contribute to the development of type 2 diabetes is not known. Cai and colleagues now show that increases in central transforming growth factor-β (TGFβ) levels induce hypothalamic inflammation and lead to hyperglycaemia and glucose intolerance — conditions that eventually may result in type 2 diabetes. Because obesity and ageing are risk factors for type 2 diabetes, the authors compared hypothalamic expression levels of several genes in mice fed a high-fat diet (HFD) versus those fed a normal chow diet, middle-aged versus young mice, and mice fed ad libitum versus calorie-restricted mice. This revealed that HFD-fed mice and middle-aged mice had higher hypothalamic Tgfb1 mRNA expression (mainly in astrocytes) than their comparison groups. By contrast, Tgfb1 mRNA levels were reduced in calorie-restricted mice. Both intraventricular injection of TGFβ1 in mice that had been fasted overnight and transgenic overexpression of Tgfb1 in astrocytes caused glucose intolerance (that is, persistently higher blood glucose levels after feeding) and insulin insensitivity (that is, a reduced ability of insulin to lower blood glucose levels) without affecting food intake or body weight. Exposure to a HFD also induced glucose intolerance and insulin resistance in control mice, but this did not occur in transgenic mice lacking astrocytic Tgfb1.
Similarly, middleaged mice showed impaired glucose tolerance and insulin sensitivity, but these impairments were reduced in middle-aged transgenic mice with reduced Tgfb1 expression (Tgfb1+/– mice). Thus, high levels of TGFβ1 in the brain seem to induce a pre-diabetic state, whereas an absence or reduction of Tgfb1 levels protects against it. The melanocortin system is known to be involved in energy homeostasis, and TGFβ1‑injected mice had reduced pro-opiomelanocortin (Pomc) mRNA expression compared with control mice. Moreover, mice lacking TGFβ receptor 2 (TGFβR2) specifically in POMC-expressing neurons developed less severe glucose intolerance and insulin resistance after HFD consumption than their control littermates. These findings suggest that POMC mediates the effects of increased levels of brain TGFβ1 on metabolic function. In previous studies, Cai and colleagues showed that obesity and ageing are associated with ‘hypo thalamic inflammation’ that is mediated by nuclear factor-κB (NF-κB). They therefore assessed whether high brain TGFβ1 levels are linked to this process. TGFβ1‑injected mice had lower mRNA and protein levels of the NF-κB inhibitor IκBα than control mice and showed evidence of hypothalamic NF-κB activation. Moreover, exposure to a 3‑week HFD increased the expression of several inflammation-related genes in the hypothalamus of wild-type mice but not in Tgfb1+/– mice, suggesting that TGFβ1 mediates HFD-induced hypothalamic inflammation.
PG /N llis a V ie Jenn
How might TGFβ1 activate hypothalamic NF-κB? The hypothalamus of TGFβ1‑injected mice and HFD-exposed mice contained more RNA stress granules (SGs) and processing bodies — indicative of an RNA stress response that induces the degradation of mRNAs — than control mice. Indeed, immunostaining experiments revealed the presence of RNA SGs in the hypothalamus of both TGFβ1‑injected mice and HFDexposed mice but not in control mice. In addition, old mice had more RNA SGs in the hypothalamus than young mice. These findings support a model in which excess central TGFβ1 induces hypothalamic inflammation by promoting IκBα degradation through an RNA stress response. Indeed, lentiviral delivery of IκBα into the hypothalamus prevented the effect of TGFβ1 injections on insulin sensitivity. By revealing a role for hypothalamic TGFβ1 and inflammation in the development of type 2 diabetes, this study may point to new therapeutic targets for this condition. Leonie Welberg ORIGINAL RESEARCH PAPER Yan, J. et al. Obesity- and aging-induced excess of central transforming growth factor-β potentiates diabetic development via an RNA stress response. Nature Med. http:dx.doi.org/10.1038/nm.3616 (2014) FURTHER READING Grayson, B. E., Seeley, R. J. & Sandoval, D. A. Wired on sugar: the role of the CNS in the regulation of glucose homeostasis. Nature Rev. Neurosci. 14, 24–37 (2013)
NATURE REVIEWS | NEUROSCIENCE
high levels of TGFβ1 in the brain seem to induce a pre-diabetic state
VOLUME 15 | SEPTEMBER 2014 © 2014 Macmillan Publishers Limited. All rights reserved
M E TA B O L I S M
Sugar on the brain Glucose homeostasis is not only regulated by the liver and pancreas; recent studies have shown that the hypothalamus also has a role in this process. However, whether changes in the hypothalamic regulation of glucose homeostasis contribute to the development of type 2 diabetes is not known. Cai and colleagues now show that increases in central transforming growth factor-β (TGFβ) levels induce hypothalamic inflammation and lead to hyperglycaemia and glucose intolerance — conditions that eventually may result in type 2 diabetes. Because obesity and ageing are risk factors for type 2 diabetes, the authors compared hypothalamic expression levels of several genes in mice fed a high-fat diet (HFD) versus those fed a normal chow diet, middle-aged versus young mice, and mice fed ad libitum versus calorie-restricted mice. This revealed that HFD-fed mice and middle-aged mice had higher hypothalamic Tgfb1 mRNA expression (mainly in astrocytes) than their comparison groups. By contrast, Tgfb1 mRNA levels were reduced in calorie-restricted mice. Both intraventricular injection of TGFβ1 in mice that had been fasted overnight and transgenic overexpression of Tgfb1 in astrocytes caused glucose intolerance (that is, persistently higher blood glucose levels after feeding) and insulin insensitivity (that is, a reduced ability of insulin to lower blood glucose levels) without affecting food intake or body weight. Exposure to a HFD also induced glucose intolerance and insulin resistance in control mice, but this did not occur in transgenic mice lacking astrocytic Tgfb1.
Similarly, middleaged mice showed impaired glucose tolerance and insulin sensitivity, but these impairments were reduced in middle-aged transgenic mice with reduced Tgfb1 expression (Tgfb1+/– mice). Thus, high levels of TGFβ1 in the brain seem to induce a pre-diabetic state, whereas an absence or reduction of Tgfb1 levels protects against it. The melanocortin system is known to be involved in energy homeostasis, and TGFβ1‑injected mice had reduced pro-opiomelanocortin (Pomc) mRNA expression compared with control mice. Moreover, mice lacking TGFβ receptor 2 (TGFβR2) specifically in POMC-expressing neurons developed less severe glucose intolerance and insulin resistance after HFD consumption than their control littermates. These findings suggest that POMC mediates the effects of increased levels of brain TGFβ1 on metabolic function. In previous studies, Cai and colleagues showed that obesity and ageing are associated with ‘hypo thalamic inflammation’ that is mediated by nuclear factor-κB (NF-κB). They therefore assessed whether high brain TGFβ1 levels are linked to this process. TGFβ1‑injected mice had lower mRNA and protein levels of the NF-κB inhibitor IκBα than control mice and showed evidence of hypothalamic NF-κB activation. Moreover, exposure to a 3‑week HFD increased the expression of several inflammation-related genes in the hypothalamus of wild-type mice but not in Tgfb1+/– mice, suggesting that TGFβ1 mediates HFD-induced hypothalamic inflammation.
PG /N llis a V ie Jenn
How might TGFβ1 activate hypothalamic NF-κB? The hypothalamus of TGFβ1‑injected mice and HFD-exposed mice contained more RNA stress granules (SGs) and processing bodies — indicative of an RNA stress response that induces the degradation of mRNAs — than control mice. Indeed, immunostaining experiments revealed the presence of RNA SGs in the hypothalamus of both TGFβ1‑injected mice and HFDexposed mice but not in control mice. In addition, old mice had more RNA SGs in the hypothalamus than young mice. These findings support a model in which excess central TGFβ1 induces hypothalamic inflammation by promoting IκBα degradation through an RNA stress response. Indeed, lentiviral delivery of IκBα into the hypothalamus prevented the effect of TGFβ1 injections on insulin sensitivity. By revealing a role for hypothalamic TGFβ1 and inflammation in the development of type 2 diabetes, this study may point to new therapeutic targets for this condition. Leonie Welberg ORIGINAL RESEARCH PAPER Yan, J. et al. Obesity- and aging-induced excess of central transforming growth factor-β potentiates diabetic development via an RNA stress response. Nature Med. http:dx.doi.org/10.1038/nm.3616 (2014) FURTHER READING Grayson, B. E., Seeley, R. J. & Sandoval, D. A. Wired on sugar: the role of the CNS in the regulation of glucose homeostasis. Nature Rev. Neurosci. 14, 24–37 (2013)
NATURE REVIEWS | NEUROSCIENCE
high levels of TGFβ1 in the brain seem to induce a pre-diabetic state
VOLUME 15 | SEPTEMBER 2014 © 2014 Macmillan Publishers Limited. All rights reserved
