Search

Complications of diabetes affect tissues throughout the body, including the central nervous system. Epidemiological studies show that diabetic patients have an increased risk of depression, anxiety, age-related cognitive decline, and Alzheimer's disease. Mice lacking insulin receptor (IR) in the brain or on hypothalamic neurons display an array of metabolic abnormalities; however, the role of insulin action on astrocytes and neurobehaviors remains less well studied. Here, we demonstrate that astrocytes are a direct insulin target in the brain and that knockout of IR on astrocytes causes increased anxiety- and depressive-like behaviors in mice. This can be reproduced in part by deletion of IR on astrocytes in the nucleus accumbens. At a molecular level, loss of insulin signaling in astrocytes impaired tyrosine phosphorylation of Munc18c. This led to decreased exocytosis of ATP from astrocytes, resulting in decreased purinergic signaling on dopaminergic neurons. These reductions contributed to decreased dopamine release from brain slices. Central administration of ATP analogs could reverse depressive-like behaviors in mice with astrocyte IR knockout. Thus, astrocytic insulin signaling plays an important role in dopaminergic signaling, providing a potential mechanism by which astrocytic insulin action may contribute to increased rates of depression in people with diabetes, obesity, and other insulin-resistant states., Introduction Over the past decade it has become clear that the brain is an insulin-sensitive organ. Insulin receptors (IRs) are widely distributed in the brain (1). Intracerebroventricular insulin infusion reduces [...]

Interactions of diet, gut microbiota, and host genetics play important roles in the development of obesity and insulin resistance. Here, we have investigated the molecular links between gut microbiota, insulin resistance, and glucose metabolism in 3 inbred mouse strains with differing susceptibilities to metabolic syndrome using diet and antibiotic treatment. Antibiotic treatment altered intestinal microbiota, decreased tissue inflammation, improved insulin signaling in basal and stimulated states, and improved glucose metabolism in obesity- and diabetes-prone C57BL/6J mice on a high-fat diet (HFD). Many of these changes were reproduced by the transfer of gut microbiota from antibiotic-treated donors to germ-free or germ-depleted mice. These physiological changes closely correlated with changes in serum bile acids and levels of the antiinflammatory bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) and were partially recapitulated by treatment with a TGR5 agonist. In contrast, antibiotic treatment of HFD-fed, obesity- resistant 129S1 and obesity-prone 129S6 mice did not improve metabolism, despite changes in microbiota and bile acids. These mice also failed to show a reduction in inflammatory gene expression in response to the TGR5 agonist. Thus, changes in bile acid and inflammatory signaling, insulin resistance, and glucose metabolism driven by an HFD can be modified by antibiotic- induced changes in gut microbiota; however, these effects depend on important interactions with the host's genetic background and inflammatory potential., Introduction Gut microbiota affect the host's energy balance, glucose and lipid metabolism, and the immune response (1). Obesity, type 2 diabetes, and metabolic syndrome are all associated with changes in [...]

Adipose tissue is a major site of energy storage and has a role in the regulation of metabolism through the release of adipokines. Here we show that mice with an adipose-tissue-specific knockout of the microRNA (miRNA)-processing enzyme Dicer (ADicerKO), as well as humans with lipodystrophy, exhibit a substantial decrease in levels of circulating exosomal miRNAs. Transplantation of both white and brown adipose tissuebrown especiallyinto ADicerKO mice restores the level of numerous circulating miRNAs that are associated with an improvement in glucose tolerance and a reduction in hepatic Fgf21 mRNA and circulating FGF21. This gene regulation can be mimicked by the administration of normal, but not ADicerKO, serum exosomes. Expression of a human-specific miRNA in the brown adipose tissue of one mouse in vivo can also regulate its 3 UTR reporter in the liver of another mouse through serum exosomal transfer. Thus, adipose tissue constitutes an important source of circulating exosomal miRNAs, which can regulate gene expression in distant tissues and thereby serve as a previously undescribed form of adipokine., Author(s): Thomas Thomou [1]; Marcelo A. Mori [2]; Jonathan M. Dreyfuss [3, 4]; Masahiro Konishi [1]; Masaji Sakaguchi [1]; Christian Wolfrum [5]; Tata Nageswara Rao [1, 6]; Jonathon N. Winnay [...]

Systemic salt loading has been reported to facilitate operant heat-escape/cold-seeking behavior. In the present study, we hypothesized that the median preoptic nucleus (MnPO) would be involved in this mechanism. Rats were divided into two groups (n = 6 each): one group had the MnPO lesion with ibotenic acid (4.0 [micro]g) and the other was the vehicle control. After subcutaneous injection (10 ml/kg) of either isotonic- (154 mM) or hypertonic-saline (2,500 mM), each rat was placed in a behavior box, where the ambient temperature was changed to 26[degrees]C, 35[degrees]C, and 40[degrees]C every 1 h. The position of a rat in the box and the body core temperature ([T.sub.core]) were monitored. A rat could trigger 0[degrees]C air for 45 s in the 35[degrees]C and 40[degrees]C heat when moved in a specific area in the box (operant behavior). In the control group, counts of the operant behavior were greater (P < 0.05) in the hypertonic- than in the isotonic-saline injection (17 [+ or -] 2 and 10 [+ or -] 2 at 35[degrees]C, 24 [+ or -] 2 and 18 [+ or -] 1 at 40[degrees]C). [T.sub.core] remained unchanged throughout the exposure, although the level was lower (P < 0.05) in the hypertonic- than in the isotonic-saline trial (36.6 [+ or -] 0.2[degrees]C and 37.4 [+ or -] 0.1[degrees]C at 26[degrees]C and 36.9 [+ or -] 0.2[degrees]C and 37.4 [+ or -] 0.1[degrees]C at 40[degrees]C, respectively). However, in the MnPO-lesion group, counts of the behavior were similar between the hypertonic- and isotonic-saline injection trials (10 [+ or -] 2 and 8 [+ or -] 1 at 35[degrees]C, and 17 [+ or -] 1 and 16 [+ or -] 1 at 40[degrees]C, respectively). [T.sub.core] increased (P < 0.05) in the heat in both trials (36.8 [+ or -] 0.1[degrees]C and 37.4 [+ or -] 0.1[degrees]C at 26[degrees]C and 37.4 [+ or -] 0.2[degrees]C and 37.8 [+ or -] 0.2[degrees]C at 40[degrees]C in the hypertonicand isotonic-saline injection trials, respectively). These results may suggest that, at least in part, the MnPO is involved in the facilitation of heat-escape/cold-seeking behavior during osmotic stimulation. osmolality; body temperature; operant behavior; lesion

The criptochrome genes (Cry1 and Cry2) are involved in the molecular mechanism that controls the circadian clock, and mice lacking these genes ([Cry1.sup.-/-]/ [Cry2.sup.-/-]) are behaviorally arrhythmic. It has been speculated that the circadian clock modulates the characteristics of thermoregulation, resulting in body temperature ([T.sub.b]) rhythm. However, there is no direct evidence proving this speculation. We show here that Tb and heat production in [Cry1.sup.-/-]/[Cry2.sup.-/-] mice are arrhythmic under constant darkness. In contrast, both rhythms occur under a light-dark cycle and/or periodical food restriction linked with spontaneous activity and/or eating, although they are not robust as those in wild-type mice. The relationship between heat production and [T.sub.b] in [Cry1.sup.-/-]/[Cry2.sup.-/-] mice is linear and identical under any conditions, indicating that their [T.sub.b] rhythm is determined by heat production rhythm associated with activity and eating. However, [T.sub.b] in wild-type mice is maintained at a relatively higher level in the active phase than the inactive phase regardless of the heat production level. These results indicate that the thermoregulatory responses are modulated according to the circadian phase, and the Cry genes are involved in this mechanism. circadian clock; thermoregulation; metabolism

Maruyama, Megumi, Maiko Nishi, Masahiro Konishi, Yuko Takashige, Kei Nagashima, Toshikazu Kiyohara, and Kazuyuki Kanosue. Brain regions expressing Fos during thermoregulatory behavior in rats. Am J Physiol Regul Integr Comp Physiol 285: R1116-R1123, 2003. First published July 31, 2003; 10.1152/ajpregu.00166.2002.--We surveyed the neural substrata for behavioral thermoregulation with immunohistochemical analysis of the expression of Fos protein in the rat brain. We used an operant system in which a rat exposed to heat (40[degrees]C) could get cold air (0[degrees]C) for 30 s when it moved into the reward area. Rats moved in and out of the reward area of the system periodically and thus maintained their body temperature at a normal level. In the rats performing heat escape behavior (active group), strong Fos immunoreactivity (Fos-IR) was found in the median preoptic nucleus (MnPO), parastrial nucleus (PS), and dorsomedial hypothalamus (DMH) compared with the controls. Another group of rats (passive group) were given the same temperature changes, regardless of the rat's movement, as those obtained by rats of the active group. Fos-IR in the MnPO was also seen in this group. The present results suggest that the PS and DMH play an important role in the genesis of thermoregulatory behavior, whereas the MnPO may be important for detecting changes in ambient and/or body temperatures. preoptic area; dorsomedial hypothalamus; operant behavior

To investigate the mechanism involved in the reduction of body core temperature ([T.sub.core]) during fasting in rats, which is selective in the light phase, we measured [T.sub.core], surface temperature, and oxygen consumption rate in fed control animals and in fasted animals on day 3 of fasting and day 4 of recovery at an ambient temperature ([T.sub.a]) of 23[degrees]C by biotelemetry, infrared thermography, and indirect calorimetry, respectively. On the fasting day, 1) [T.sub.core] in the light phase decreased (P < 0.05) from the control; however, [T.sub.core] in the dark phase was unchanged, 2) tail temperature fell from the control (P < 0.05, from 30.7 [+ or -] 0.1 to 23.9 [+ or -] 0.1[degrees]C in the dark phase and from 29.4 [+ or -] 0.1 to 25.2 [+ or -] 0.2[degrees]C in the light phase), 3) oxygen consumption rate decreased from the control (P < 0.05, from 24.37 [+ or -] 1.06 to 16.24 [+ or -] 0.69 ml*[min.sup.-1]* kg body [wt.sup.-0.75] in the dark phase and from 18.91 [+ or -] 0.64 to 14.00 [+ or -] 0.41 ml*[min.sup.-1]*kg body [wt.sup.-0.75] in the light phase). All these values returned to the control levels on the recovery day. The results suggest that, in the fasting condition, [T. sub.core] in the dark phase was maintained by suppression of the heat loss mechanism, despite the reduction of metabolic heat production. In contrast, the response was weakened in the light phase, decreasing [T.sub.core] greatly. Moreover, the change in the regulation of tail blood flow was a likely mechanism to suppress heat loss. core temperature; oxygen consumption; heat loss mechanism

Author(s): Thomas Thomou; Marcelo A. Mori; Jonathan M. Dreyfuss; Masahiro Konishi; Masaji Sakaguchi; Christian Wolfrum; Tata Nageswara Rao; Jonathon N. Winnay; Ruben Garcia-Martin; Steven K. Grinspoon; Phillip Gorden; C. Ronald [...]

Nagashima, Kei, Sadamu Nakai, Masahiro Konishi, Liu Su, and Kazuyuki Kanosue. Increased heat-escape/ cold-seeking behavior following hypertonic saline injection in rats. Am J Physiol Regulatory Integrative Comp Physiol 280: R1031-R1036, 2001.--We examined the effect of hypertonic saline injection on heat-escape/cold-seeking behavior in desalivated rats. Rats were exposed to 40 [degrees] C heat after normal (154 mM NaCl, control) or hypertonic saline (2,500 mM NaC1) injection (1 ml/100 g body wt). The rats received a 0 [degrees] C air for 30 s when they entered a specific area in an experimental box. Core temperature ([T.sub.c]) surpassed 40 [degrees] C in both conditions when 0 [degrees] C air was not available. Hypertonic saline injection produced a lower baseline [T.sub.c] than control [36.9 [+ or -] 0.2 and 37.9 [+ or -] 0.2 [degrees] C (means [+ or -] SE), P [is less than] 0.05] and a greater number of 0 [degrees] C air rewards during the 2-h heat with lower [T.sub.c] at the end (48 [+ or -] 1 and 34 [+ or -] 2, 37.6 [+ or -] 0.1, and 37.3 [+ or -] 0.1 [degrees] C in the control and hypertonic saline injection trial, respectively, P [is less than] 0.05, n = 6). However, Tc was similar (37.7 [+ or -] 0.2 and 37.6 [+ or -] 0.4 [degrees] C in the control and hypertonic saline injection trial, n = 5) when 0 [degrees] C air was automatically and intermittently (35 times) given during the heat. Rats augment heat-defense mechanisms in response to osmotic stress by lowering the baseline [T.sub.c] and increasing heat-escape/coldseeking behavior. hyperosmolality; operant behavior; desalivation