The Effect of Cancer Cachexia Progression on the Feeding Regulation of Skeletal Muscle Protein Turnover

Cancer cachexia is defined as the unintentional loss of skeletal muscle mass with or without fat loss that cannot be reversed by conventional nutritional support. Cachexia occurs in ~20% of cancer patients. More specifically, 50% of lung cancer patients, the most common cancer worldwide, develop cachexia. Cachexia occurs most often in lung and gastrointestinal cancers, whereas breast and prostate have the lowest rate of cachexia. Cancer-induced cachexia disrupts skeletal muscle protein turnover (decreasing protein synthesis and increasing protein degradation). Skeletal muscle’s capacity for protein synthesis is highly sensitive to local and systemic stimuli that are controlled by mTORC1 and AMPK signaling. During cachexia, altered protein turnover is thought to occur through suppressed anabolic signaling via mTORC1, coinciding with the chronic activation of AMPK. While progress has been made in understanding some of the mechanisms underlying the suppressed anabolic signaling in cachectic muscle, gaps still remain in our understanding of muscle’s ability to respond to anabolic stimulus prior to cachexia development. The purpose of this study was to determine if cachexia progression disrupts the feeding regulation of AMPK signaling and if gp130 signaling and muscle contraction could regulate this process. Specific aim 1 examined the feeding regulation of skeletal muscle protein synthesis in pre-cachectic tumor bearing mice. Feeding increased muscle protein synthesis, while lowering AMPK signaling in pre-cachectic tumor bearing mice. Importantly, pre-cachectic tumor bearing mice have overall suppressed muscle protein synthesis independent of the fast or fed condition. Muscle specific AMPK loss was sufficient to improve the fasting suppression of muscle mTORC1 and protein synthesis in pre-cachectic tumor bearing mice. Specific aim 2 examined if muscle gp130 signaling regulates the feeding regulation of AMPK during cancer cachexia progression. Muscle gp130 loss lowered the fasting induction of AMPK in pre-cachectic tumor bearing mice without improving protein synthesis. Muscle gp130 loss did not alter the feeding regulation of muscle Akt/mTORC1 signaling and protein synthesis. Specific Aim 3 examined if an acute bout of muscle contractions could improve the muscle protein synthesis response to feeding during the progression of cachexia. Pre-cachectic tumor bearing mice exhibit suppressed protein synthesis in response low frequency electrical stimulation, and the inability to synergistically induce protein synthesis in response to feeding and contraction. In summary, pre-cachectic tumor bearing mice have lowered Akt/mTORC1 signaling and protein synthesis. Feeding can induce Akt/mTORC1 and protein synthesis and AMPK regulates the fasting suppression of protein synthesis in pre-cachectic tumor bearing mice. While gp130 loss reduces AMPK it is not sufficient to improve protein synthesis in pre-cachectic tumor bearing mice. The added protein synthesis response to feeding and contraction is blunted in pre-cachectic tumor bearing mice. These findings provide novel insight into the regulation of Akt/mTORC1 signaling and protein synthesis in response to feeding. Additionally, these studies highlight gp130’s regulation of AMPK prior to cachexia development, and the blunted anabolic muscle response to feeding and contraction in pre-cachectic tumor bearing mice. By understanding these intracellular signaling processes and perturbations prior to cachexia development, we will be able to elucidate potential therapeutic targets and treatment options to manipulate and prevent cancer cachexia.

Correlation between maternal eating disorder and early infant feeding regulation: a cross -sectional study

Background The post-partum period is a vulnerable time for mothers in terms of eating disorder symptoms and is critical for the establishment of feeding patterns in infants. This study aimed to investigate the relationships between maternal eating disorder symptoms and objective indices of feeding regulation at 3 months, as well as perceived breastfeeding self-efficacy. Methods A sample of n = 73 full-term mother-child dyads (44% female) participated in the study. Mothers self-reported eating disorder symptoms and breastfeeding self-efficacy and objective indices of infant feeding regulation were obtained in the home. Results Findings revealed the existence of relationships between higher maternal eating disorder symptoms, and objective indices of infant feeding regulation with substantial gender differences in the patterns emerging. Among mother-daughter dyads, maternal weight and shape concerns were associated with higher infant transfer volume and rate during bottle feeding. In contrast, among mother-son dyads, higher maternal eating disorder symptoms, including weight, shape, and eating concern, were associated with lower infant transfer volume and rate as well as lower levels of proficiency while taking their bottle. Conclusion Relationships emerged between higher maternal eating disorder symptoms and feeding regulation with substantial gender differences in these patterns. Additional research clarifying the underlying mechanisms of these associations is warranted and further efforts should be directed towards supporting mothers during the postpartum period.

Proteome Analysis of the Hypothalamic Arcuate Nucleus in Chronic High-Fat Diet-Induced Obesity

The hypothalamus plays a central role in the integrated regulation of feeding and energy homeostasis. The hypothalamic arcuate nucleus (ARC) contains a population of neurons that express orexigenic and anorexigenic factors and is thought to control feeding behavior via several neuronal circuits. In this study, a comparative proteomic analysis of low-fat control diet- (LFD-) and high-fat diet- (HFD-) induced hypothalamic ARC was performed to identify differentially expressed proteins (DEPs) related to changes in body weight. In the ARC in the hypothalamus, 6621 proteins ( FDR < 0.01 ) were detected, and 178 proteins were categorized as DEPs (89 upregulated and 89 downregulated in the HFD group). Among the Gene Ontology molecular function terms associated with the DEPs, protein binding was the most significant. Fibroblast growth factor receptor substrate 2 (Frs2) and SHC adaptor protein 3 (Shc3) were related to protein binding and involved in the neurotrophin signaling pathway according to Kyoto Encyclopedia of Genes and Genomes analysis. Furthermore, high-precision quantitative proteomic analysis revealed that the protein profile of the ARC in mice with HFD-induced obesity differed from that in LFD mice, thereby offering insight into the molecular basis of feeding regulation and suggesting Frs2 and Shc3 as novel treatment targets for central anorexigenic signal induction.

Comparative Study of the Feeding Characteristics and Digestion Physiology of Haliotis discus hannai and Haliotis gigantea

Abalone (Haliotis spp.) are typical nocturnal creatures but Haliotis discus hannai is bold and active in the nighttime whereas H. gigantea tends to be timid and inactive. In this study, we quantified and compared differences in movement, feeding, and digestive physiology between H. discus hannai and H. gigantea as well as the potential molecular mechanisms on the basis of video observations and expression levels of genes related to feeding regulation. The feeding behaviors of both species were characterized by significant circadian rhythms (P &lt; 0.05). However, the distance moved and the cumulative duration of movement were 2.61 and 1.94 times higher, respectively, in H. discus hannai than in H. gigantea over the 24-h cycle. The cumulative duration of feeding by H. discus hannai was only 1.15 times that by H. gigantea, but the feeding time as a percentage of the cumulative duration of movement (FTP) was up to 94.6% for H. gigantea and only 56.0% for H. discus hannai. The peaks for α-amylase activity and NPF expression levels in both species as well as the peak OX2R expression level in H. gigantea occurred during 20:00–00:00 h. By contrast, the peaks for alginate lyase activity and NPYR expression levels in H. discus hannai occurred at 16:00 h, when the FTP was significantly higher for H. discus hannai than for H. gigantea. These initial findings quantify specific behavior parameters and thus provide a reference for the selection of appropriate feeding strategies and the proliferation of abalone via bottom sowing.

Bombesin receptors in GtoPdb v.2021.2

Mammalian bombesin (Bn) receptors comprise 3 subtypes: BB1, BB2, BB3 (nomenclature recommended by the NC-IUPHAR Subcommittee on bombesin receptors, [115]). BB1 and BB2 are activated by the endogenous ligands neuromedin B (NMB), gastrin-releasing peptide (GRP), and GRP-(18-27). bombesin is a tetra-decapeptide, originally derived from amphibians. The three Bn receptor subtypes couple primarily to the Gq/11 and G12/13 family of G proteins [115]. Each of these receptors is widely distributed in the CNS and peripheral tissues [78, 115, 249, 278, 237, 362]. Activation of BB1 and BB2 receptors causes a wide range of physiological/pathophysiogical actions, including the stimulation of normal and neoplastic tissue growth, smooth-muscle contraction, gastrointestinal motility, feeding behavior, secretion and many central nervous system effects including regulation of circadian rhythm, body temperature control, sighing and mediation of pruritus [149, 202, 244, 115, 196, 249, 306, 68, 34, 332]. A physiological role for the BB3 receptor has yet to be fully defined although recently studies suggest an important role in glucose and insulin regulation, metabolic homeostasis, feeding, regulation of body temperature, obesity, diabetes mellitus and growth of normal/neoplastic tissues [148, 78, 162, 214, 346, 200]. Bn receptors are one of the most frequently overexpressed receptors in cancers and are receiving increased attention for their roles in tumor growth, as well as for tumour imaging and for receptor targeted cytotoxicity [202, 276, 8, 161].

Deciphering an AgRP-serotoninergic neural circuit in distinct control of energy metabolism from feeding

Contrasting to the established role of the hypothalamic agouti-related protein (AgRP) neurons in feeding regulation, the neural circuit and signaling mechanisms by which they control energy expenditure remains unclear. Here, we report that energy expenditure is regulated by a subgroup of AgRP neurons that send non-collateral projections to neurons within the dorsal lateral part of dorsal raphe nucleus (dlDRN) expressing the melanocortin 4 receptor (MC4R), which in turn innervate nearby serotonergic (5-HT) neurons. Genetic manipulations reveal a bi-directional control of energy expenditure by this circuit without affecting food intake. Fiber photometry and electrophysiological results indicate that the thermo-sensing MC4RdlDRN neurons integrate pre-synaptic AgRP signaling, thereby modulating the post-synaptic serotonergic pathway. Specifically, the MC4RdlDRN signaling elicits profound, bi-directional, regulation of body weight mainly through sympathetic outflow that reprograms mitochondrial bioenergetics within brown and beige fat while feeding remains intact. Together, we suggest that this AgRP neural circuit plays a unique role in persistent control of energy expenditure and body weight, hinting next-generation therapeutic approaches for obesity and metabolic disorders.

Functional Interaction of Spexin and Adiponectin Forming a Local Feedbackin Goldfish Hepatocytes for Feeding Regulation

Spexin (SPX), a neuropeptide with pleiotropic functions, has been confirmed to be a novel satiety factor in fish models. Adiponectin (AdipoQ), the most abundant adipokine in circulation, is involved in lipid and glucose metabolism and its insulin-sensitizing, cardioprotective, and anti-inflammatory actions are also well-documented. However, the interaction between SPX and AdipoQ has not be reported and very little is known regarding the functions of AdipoQ in non-mammalian species. In this study, AdipoQ was cloned in goldfish and found to be widely expressed at tissue level including the liver. Sequence alignment and in silico protein modelling revealed that its a.a. sequence and 3D protein structure were highly comparable to the mammalian counterparts. Recombinant protein of goldfish AdipoQ was expressed in E. coli and IP injection of the protein purified could suppress foraging activity and food intake in goldfish. Food intake in goldfish, interestingly, could elevate plasma levels of SPX and AdipoQ with parallel rises of their transcript expression in the liver. In primary culture of goldfish hepatocytes, SPX treatment was shown to induce protein phosphorylation of MEK1/2 and ERK1/2 with a parallel rise in AdipoQ mRNA level. SPX-induced AdipoQ mRNA expression, however, was sensitive to the blockade of PLC/PKC, Ca2+/CaMK-II and MEK1/2/ERK1/2 but not cAMP/PKA cascades. In reciprocal experiments, AdipoQ treatment could induce protein phosphorylation of AMPK, Akt and P38 MAPK in goldfish hepatocytes. Meanwhile, AdipoQ was also effective in reducing SPX mRNA level and this inhibitory effect was negated by blocking the AMPK/PPAR, PI3K/Akt and P38 MAPK but not the MEK1/2/ERK1/2 or PLC/PKC pathways. Apparently, the PI3K/Akt and P38 MAPK cascades were functionally coupled with AMPK activation. These results imply that (i) AdipoQ, similar to SPX, can be induced by food intake and serve as a satiety signal in goldfish, (ii) AdipoQ expression in goldfish liver can be up-regulated by SPX via the PLC/PKC, Ca2+/CaMK-II and MEK1/2/ERK1/2 pathways, which may enhance the satiation response caused by SPX after food intake, and (iii) AdipoQ can inhibit SPX expression at hepatic level via the AMPK/PPAR, PI3K/Akt and P38 MAPK cascades, which may lead to signal termination of SPX. These findings, as a whole, suggest that AdipoQ production in goldfish liver not only can form a signal amplification step for the satiation response of SPX but also constitute a local feedback to turn off SPX signal at the hepatic level.

A distinct parabrachial–to–lateral hypothalamus circuit for motivational suppression of feeding by nociception

The motivation to eat is not only shaped by nutrition but also competed by external stimuli including pain. How the mouse hypothalamus, the feeding regulation center, integrates nociceptive inputs to modulate feeding is unclear. Within the key nociception relay center parabrachial nucleus (PBN), we demonstrated that neurons projecting to the lateral hypothalamus (LHPBN) are nociceptive yet distinct from danger-encoding central amygdala–projecting (CeAPBN) neurons. Activation of LHPBN strongly suppressed feeding by limiting eating frequency and also reduced motivation to work for food reward. Refined approach-avoidance paradigm revealed that suppression of LHPBN, but not CeAPBN, sustained motivation to obtain food. The effect of LHPBN neurons on feeding was reversed by suppressing downstream LHVGluT2 neurons. Thus, distinct from a circuit for fear and escape responses, LHPBN neurons channel nociceptive signals to LHVGluT2 neurons to suppress motivational drive for feeding. Our study provides a new perspective in understanding feeding regulation by external competing stimuli.

Amylin Inhibits the Feeding of the Siberian Sturgeon

Amylin is a 37-amino acid polypeptide that has been shown to be involved in feeding regulation in a few mammals, birds and goldfish. To study whether amylin regulates the feeding of Siberian sturgeon, this study cloned amylin of Siberian sturgeon and detected the distribution pattern of amylin in 15 tissues, the expression level in periprandial (pre- and post-feeding), and the changes of food intake and related appetite factors after intraperitonal injection experiment. The results showed that the expression of amylin was highest in hypothalamus, followed by duodenum, telencephalon, forebrain, midbrain, heart and liver, and low in cerebellum, pancreas, valvular intestine and other detection tissues. Compared with 1h pre-feeding, the expression level of amylin in hypothalamus was significantly increased at 1h post-feeding (P < 0.05), and the expression level of amylin in duodenum was extremely significantly increased at 1h post-feeding (P < 0.01). Compared with the control group (normal saline), the food intake at 0-1h and 1-3h after intraperitoneal injection of 100 ng/g BW and 200 ng/g BW was significantly decreased (P < 0.05), and the food intake at 3-6h in 100 ng/g BW group was extremely significantly decreased (P < 0.01), and the food intake at 3-6h in 200 ng/g BW group was significantly decreased (P < 0.05). After 1h of injection of 100 ng/g amylin, MC4R in hypothalamus was significantly increased (P < 0.05) and somatostatin was extremely significantly increased (P < 0.01), while amylin and NPY were significantly decreased (P < 0.05). CCK in valvular intestine was extremely significantly increased (P < 0.01), insulin in duodenum was significantly increased (P < 0.05), but ghrelin in duodenum had no significant change (P > 0.05). These results showed that Amylin inhibited feeding in Siberian sturgeon by down-regulating appetite stimulating factor NPY and up-regulating appetite suppressing factors somatostatin , MC4R , CCK and insulin .

Neuroanatomical organization and functional roles of PVN MC4R pathways in physiological and behavioral regulations

ABSTRACTObjectiveThe paraventricular nucleus of hypothalamus (PVN) is an integrative center in the brain orchestrating a wide range of physiological and behavioral responses. While the PVN melanocortin 4 receptor (MC4R) signaling (PVNMC4R+) is undoubtedly involved in feeding regulation, the neuroanatomical organization of PVNMC4R+ pathway and its role in diverse physiological and behavioral regulations have not been fully understood. Here we aimed to better characterize the input-output organization of PVNMC4R+ neurons and further test their potential functional roles beyond feeding.MethodsUsing a combination of viral tools, we performed a comprehensive mapping of PVNMC4R+ circuits and tested the effects of chemogenetic activation of PVNMC4R+ neurons on thermogenesis, cardiovascular control and other behavioral regulations beyond feeding.ResultsWe found that PVNMC4R+ neurons broadly innervate many different brain regions known to be important not only for feeding but also for neuroendocrine and autonomic control of thermogenesis and cardiovascular function, including but not limited to preoptic area, median eminence, parabrachial nucleus, locus coeruleus, nucleus of solitary tract, ventrolateral medulla and thoracic spinal cord. Contrary to broad efferent projections, PVNMC4R+ neurons receive monosynaptic inputs from limited brain regions, including medial preoptic nucleus, arcuate and dorsomedial hypothalamic nuclei, and supraoptic nucleus. Consistent with broad efferent projections, chemogenetic activation of PVNMC4R+ neurons not only suppressed feeding but also led to an apparent increase in heart rate, blood pressure and brown adipose tissue thermogenesis. Strikingly, these physiological changes accompanied an unexpected repetitive bedding-removing behavior followed by hypoactivity and resting-like behavior.ConclusionsOur results clarify the neuroanatomical organization of PVNMC4R+ circuits and shed new light on the roles of PVNMC4R+ pathways in autonomic control of thermogenesis, cardiovascular function and other behavioral regulations.