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The melanocortin action is well perceived for its ability to regulate body weight bidirectionally with its gain of function reducing body weight and loss of function promoting obesity. However, this notion cannot explain the difficulty in identifying effective therapeutics toward treating general obesity via activation of the melanocortin action. Here, we provide evidence that altered melanocortin action is only able to cause one-directional obesity development. We demonstrate that chronic inhibition of arcuate neurons expressing proopiomelanocortin (POMC) or paraventricular hypothalamic neurons expressing melanocortin receptor 4 (MC4R) causes massive obesity. However, chronic activation of these neuronal populations failed to reduce body weight. Furthermore, gain of function of the melanocortin action through overexpression of MC4R, POMC or its derived peptides had little effect on obesity prevention or reversal. These results reveal a bias of the melanocortin action towards protection of weight loss and provide a neural basis behind the well-known, but mechanistically ill-defined, predisposition to obesity development. Melanocortin action is known to regulate body weight. Here the authors report that while inhibition of the hypothalamic melanocortin action leads to obesity in mice, chronic activation of melanocortin action is not sufficient to cause weight loss. [ABSTRACT FROM AUTHOR]

This paper proposes a joint estimation scheme for the state of charge (SoC) and state of health (SoH) for lithium-ion batteries in electric vehicles. The estimation accuracy is improved from four aspects. First, to overcome the shortcomings of the electrochemical model and equivalent circuit model, the battery model is established by a fractional order (FO) model. Second, a genetic algorithm is used to identify the model parameters, realizing optimal parameter identification. Third, the FO adaptive extended Kalman filter-based SoC estimator is developed, and the innovation accuracy of the algorithm is improved by multi- innovation theory. Fourth, the joint estimation of SoC and SoH is formulated through a multi-timescale framework. The proposed model and method are verified through dynamic operating condition experiments, and the main results are as follows. (1) In the entire SoC range, the accuracy of the FO model is better than that of the integer order (IO) model. (2) The effectiveness of the optimized SoC estimation method is verified, and the estimation error can be controlled within 3%. (3) The effectiveness of the proposed joint estimation method in dynamic conditions is verified, and it shows high accuracy. [ABSTRACT FROM AUTHOR]

Central leptin action rescues type 1 diabetic (T1D) hyperglycemia; however, the underlying mechanism and the identity of mediating neurons remain elusive. Here, we show that leptin receptor (LepR)-expressing neurons in arcuate (LepRArc) are selectively activated in T1D. Activation of LepRArc neurons, Arc GABAergic (GABAArc) neurons, or arcuate AgRP neurons, is able to reverse the leptin's rescuing effect. Conversely, inhibition of GABAArc neurons, but not AgRP neurons, produces leptin-mimicking rescuing effects. Further, AgRP neuron function is not required for T1D hyperglycemia or leptin's rescuing effects. Finally, T1D LepRArc neurons show defective nutrient sensing and signs of cellular energy deprivation, which are both restored by leptin, whereas nutrient deprivation reverses the leptin action. Our results identify aberrant activation of LepRArc neurons owing to energy deprivation as the neural basis for T1D hyperglycemia and that leptin action is mediated by inhibiting LepRArc neurons through reversing energy deprivation. Leptin can rescue hyperglycemia in type 1 diabetes, but the underlying mechanisms for this effect are not clear. Here, the authors report that leptin action is mediated by inhibition of the heightened activity of arcuate GABA neurons in murine models of type 1 diabetes through restoring nutrient sensing. [ABSTRACT FROM AUTHOR]

Defective rhythmic metabolism is associated with high-fat high-caloric diet (HFD) feeding, ageing and obesity; however, the neural basis underlying HFD effects on diurnal metabolism remains elusive. Here we show that deletion of BMAL1, a core clock gene, in paraventricular hypothalamic (PVH) neurons reduces diurnal rhythmicity in metabolism, causes obesity and diminishes PVH neuron activation in response to fast-refeeding. Animal models mimicking deficiency in PVH neuron responsiveness, achieved through clamping PVH neuron activity at high or low levels, both show obesity and reduced diurnal rhythmicity in metabolism. Interestingly, the PVH exhibits BMAL1-controlled rhythmic expression of GABA-A receptor γ2 subunit, and dampening rhythmicity of GABAergic input to the PVH reduces diurnal rhythmicity in metabolism and causes obesity. Finally, BMAL1 deletion blunts PVH neuron responses to external stressors, an effect mimicked by HFD feeding. Thus, BMAL1-driven PVH neuron responsiveness in dynamic activity changes involving rhythmic GABAergic neurotransmission mediates diurnal rhythmicity in metabolism and is implicated in diet-induced obesity. Defective rhythmic metabolism is associated with high-fat diet feeding and obesity. The authors show that the clock gene BMAL1 drives paraventricular hypothalamic neuron activity via rhythmic GABAergic neurotransmission, and that this mediates diurnal metabolism and diet-induced obesity. [ABSTRACT FROM AUTHOR]

Feeding is known to be profoundly affected by stress-related emotional states and eating disorders are comorbid with psychiatric symptoms and altered emotional responses. The neural basis underlying feeding regulation by stress-related emotional changes is poorly understood. Here, we identify a novel projection from the paraventricular hypothalamus (PVH) to the ventral lateral septum (LSv) that shows a scalable regulation on feeding and behavioral changes related to emotion. Weak photostimulation of glutamatergic PVH→LSv terminals elicits stress-related self-grooming and strong photostimulation causes fear-related escape jumping associated with respective weak and strong inhibition on feeding. In contrast, inhibition of glutamatergic inputs to LSv increases feeding with signs of reduced anxiety. LSv-projecting neurons are concentrated in rostral PVH. LSv and LSv-projecting PVH neurons are activated by stressors in vivo, whereas feeding bouts were associated with reduced activity of these neurons. Thus, PVH→LSv neurotransmission underlies dynamic feeding by orchestrating emotional states, providing a novel neural circuit substrate underlying comorbidity between eating abnormalities and psychiatric disorders. Eating disorders are often comorbid with emotional and psychiatric symptoms yet the underlying neural circuits are poorly understood. Here, the authors report that projections from the paraventricular hypothalamus to the ventral part of the lateral septum regulates both feeding and behavioral responses to stress. [ABSTRACT FROM AUTHOR]

The current obesity epidemic faces a lack of mechanistic insights. It is known that the acute activity changes of a growing number of brain neurons rapidly alter feeding behaviour; however, how these changes translate to obesity development and the fundamental mechanism underlying brain neurons in controlling body weight remain elusive. Here, we show that chronic activation of hypothalamic arcuate GABAergic (GABA + ), agouti-related protein (AgRP) neurons or arcuate non-AgRP GABA +  neurons leads to obesity, which is similar to the obese phenotype observed in ob/ob mice. Conversely, chronic inhibition of arcuate GABA + , but not AgRP, neurons reduces ageing-related weight gain and corrects ob/ob obesity. These results demonstrate that the modulation of Arc GABA +  neuron activity is a fundamental mechanism of body-weight regulation, and that arcuate GABA +  neurons are the major mediator of leptin action, with a profound and redundant role in obesity development.