Biology subjects

Leinninger, G. M.

Publications and source records attributed to Leinninger, G. M..

4 recordsLinked to original sources

bioRxiv2026

Biased signaling via NtsR1 restrains food intake and weight gain in obese mice

Neurotensin receptor 1 (NTSR1) activation suppresses feeding and promotes weight loss but is limited by adverse effects associated with Gq signaling. SBI-553 is a {beta}-arrestin-biased allosteric modulator of NTSR1 that avoids these effects. We evaluated the effects of SBI-553 (5 or 12 mg/kg, i.p.) on food intake and body weight in lean and diet-induced obese mice. Neither dose altered metabolic parameters, locomotor activity, or wheel running. SBI-553 did not affect ad libitum feeding in lean mice; however, both doses acutely reduced high-fat diet intake in obese mice. While 5 mg/kg had no effect on hunger-induced feeding, 12 mg/kg suppressed refeeding in both chow- and high-fat-fed mice of both sexes and reduced weight regain in obese mice. These findings identify SBI-553 as a potential strategy for reducing food intake and supporting weight loss.

physiology↗

bioRxiv2026

Biased signaling at NTSR1 differentially regulates inhibitory synaptic transmission in the extended amygdala and suppresses motivated feeding in mice

Maladaptive consummatory behaviors can arise from dysregulated circuits, like those in the extended amygdala, governing motivation and feeding behaviors. Neurotensin (NTS), expressed throughout the central, peripheral, and enteric nervous systems, has well-established roles in energy balance and feeding. SBI-553, a biased allosteric modulator of NTSR1, recruits {beta}-arrestin while attenuating Gq-mediated signaling. We used SBI-553 to examine NTS modulation GABAergic signaling in the central amygdala (CeA) and bed nucleus of the stria terminalis (BNST) and probed its effects on food consumption in mice. We found that NTS and SBI-553 differentially modulate GABAergic neurotransmission across extended amygdala subregions. In vivo, SBI-553 reduces palatable food consumption in both fed and food-deprived mice, with greater reductions under fasted conditions, altering activation across CeA subregions in a sex- and feeding-state-dependent manner. In the BNST, differences in SBI-553 altered cFos activity were observed between feeding states. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=157 SRC="FIGDIR/small/722083v3_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@1825c16org.highwire.dtl.DTLVardef@16be6acorg.highwire.dtl.DTLVardef@f5561eorg.highwire.dtl.DTLVardef@e8f82c_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LINTS enhances GABAergic transmission in the CeAL and the ovBNST C_LIO_LISBI-553 blocks NTS-induced increases in sIPSC frequency in the CeAL but not in the ovBNST C_LIO_LISBI-553 attenuates the feeding of a palatable high-carbohydrate food C_LIO_LIThe effect of SBI-553 on feeding is driven by energy deficit/motivation to feed C_LI

neuroscience↗

bioRxiv2022

Sex-dependent role of hypocretin/orexin neurons in social behavior

Intraspecies social interactions are integral for survival and maintenance of society among all mammalian species. Yet, our understanding of the neural systems and mechanisms involved in the establishment of social connectedness are limited. Since their initial discovery as regulators of sleep/wakefulness and appetite in the brain, the hypocretin/orexin neurons have also been shown to play an essential role in modulating energy homeostasis, motivated and emotional behavior. These neurons are located exclusively in the hypothalamus which, regulates complex and goal-directed behaviors. The hypothalamus also plays an important role in the modulation of social behavior by encoding internal states. However, our understanding of the role of hypocretin neurons in social behavior is currently limited. To address this knowledge gap, we performed a combination of fiber photometry and machine learning based behavioral analysis in female and male mice expressing GCaMP6s in hypocretin neurons. We then applied optogenetic and pharmacological inhibition of hypocretin neuron signaling to determine the necessity of the hcrt neuron population for social behavior. Our results indicate that hypocretin neurons exhibit a robust increase in activity in response to social interaction in both female and male mice. We show here for the first time a social discrimination signal that is encoded differentially by hcrt neurons based on the nature of the social encounter. The intensity of the hcrt neuron activity predicts the subsequent duration of social interaction. The optogenetic inhibition of hypocretin neuron activity during social behavior leads to a reduction in the amount of time mice are engaged in social interaction in males but not in females. Blocking hcrt1 (orexin 1) receptors similarly reduces social interaction in males only. Reduced hcrt1 receptor signaling results in increased activity in the insular cortex and reduced activity in the VTA after social interaction in male mice. Together, these data implicate the lateral hypothalamus hypocretin neurons as a sexually dimorphic key regulator within the larger network of neural systems involved in social behavior. Our findings carry significant implications for the treatment of neuropsychiatric diseases characterized by social dysfunction, particularly considering the varying prevalence observed across different sexes.

neuroscience↗

bioRxiv2021

Depleting Hypothalamic Somatostatinergic Neurons Recapitulates Diabetic Phenotypes in Brain, Bone Marrow, Adipose, and Retina

Hypothalamic inflammation and sympathetic nervous system hyperactivity are hallmark features of metabolic syndrome and type 2 diabetes. Hypothalamic inflammation may aggravate metabolic and immunologic pathologies due to extensive sympathetic activation of peripheral tissues. Loss of somatostatinergic (SST) neurons may contribute to enhanced hypothalamic inflammation. The present data show that leptin receptor deficient (db/db) mice exhibit reduced hypothalamic somatostatinergic cells, particularly in the periventricular nucleus. We model this finding, using adeno-associated virus (AAV) delivery of diphtheria toxin (DTA) driven by an SST-cre system to deplete these cells in SSTcre/gfp mice (SST-DTA). SST-DTA mice exhibit enhanced hypothalamic c-fos expression and brain inflammation as demonstrated by microglial and astrocytic activation. Bone marrow from SST-DTA mice undergoes skewed hematopoiesis, generating excess granulocyte-monocyte precursors and increased pro-inflammatory (CCR2hi) monocytes. Visceral adipose tissue from DTA-treated animals was resistant to catecholamine induced lipolysis. Finally, SST-DTA mice exhibited a "diabetic retinopathy like" phenotype: reduced visual function by optokinetic response and electroretinogram, as well as increased percentages of retinal monocytes. Importantly, hyperglycemia was not observed in SST-DTA mice. Thus, the isolated reduction in hypothalamic somatostatinergic neurons was able to recapitulate several hallmark features of type 2 diabetes in disease relevant tissues.

neuroscience↗