Spexin modulates molecular thermogenic profile of adipose tissue and thermoregulatory behaviors in female C57BL/6 mice.

Thermoregulation is the physiological process by which an animal regulates body temperature in response to its environment. It is known that galanin, a neuropeptide widely distributed throughout the central nervous system and secreted by the gut, plays a role in thermoregulatory behaviors and metabolism. We tested the ability of the novel neuropeptide spexin, which shares sequence homology to galanin, to regulate these functions in female mice. Supraphysiological levels of spexin in C57BL/6 mice did not lead to weight loss after 50 days of treatment. Behavioral analysis of long-term spexin treatment showed it decreased anxiety and increased thermoregulatory nest building, which was not observed when mice were housed at thermoneutral temperatures. Treatment also disrupted the thermogenic profile of brown and white adipose tissue, decreasing mRNA expression of Ucp1 in BAT and immunodetection of ß3-adrenergic receptors in gWAT. Our results reveal novel functions for spexin as a modulator of thermoregulatory behaviors and adipose tissue metabolism.

From Parental Behavior to Sexual Function: Recent Advances in Oxytocin Research.

Purpose of Review: Oxytocin plays many diverse roles in physiological and behavioral processes, including social activity, parental nurturing, stress responses, and sexual function. In this narrative review, we provide an update on the most noteworthy recent findings in this fascinating field. Recent Findings: The development of techniques such as serial two-photon tomography and fiber photometry have provided a window into oxytocin neuroanatomy and real-time neuronal activity during social interactions. fMRI and complementary mapping techniques offer new insights into oxytocin's influence on brain activity and connectivity. Indeed, oxytocin has recently been found to influence the acquisition of maternal care behaviors and to mediate the influence of social touch on brain development and social interaction. Additionally, oxytocin plays a crucial role in male sexual function, affecting erectile activity and ejaculation, while its role in females remains controversial. Recent studies also highlight oxytocin's interaction with other neuropeptides, such as melanin-concentrating hormone, serotonin, and arginine vasopressin, influencing social and affective behaviors. Finally, an update is provided on the status of clinical trials involving oxytocin as a therapeutic intervention. Summary: The exploration of oxytocin's complexities and its interplay with other neuropeptides holds promise for targeted treatment in various health and disease contexts. Overall, these findings contribute to the discovery of new and specific pathways to allow therapeutic targeting of oxytocin to treat disorders.

Melanocortin 4 receptor signaling in Sim1 neurons permits sexual receptivity in female mice.

Introduction: Female sexual dysfunction affects approximately 40% of women in the United States, yet few therapeutic options exist for these patients. The melanocortin system is a new treatment target for hypoactive sexual desire disorder (HSDD), but the neuronal pathways involved are unclear. Methods: In this study, the sexual behavior of female MC4R knockout mice lacking melanocortin 4 receptors (MC4Rs) was examined. The mice were then bred to express MC4Rs exclusively on Sim1 neurons (tbMC4RSim1 mice) or on oxytocin neurons (tbMC4ROxt mice) to examine the effect on sexual responsiveness. Results: MC4R knockout mice were found to approach males less and have reduced receptivity to copulation, as indicated by a low lordosis quotient. These changes were independent of body weight. Lordosis behavior was normalized in tbMC4RSim1 mice and improved in tbMC4ROxt mice. In contrast, approach behavior was unchanged in tbMC4RSim1 mice but greatly increased in tbMC4ROxt animals. The changes were independent of melanocortin-driven metabolic effects. Discussion: These results implicate MC4R signaling in Oxt neurons in appetitive behaviors and MC4R signaling in Sim1 neurons in female sexual receptivity, while suggesting melanocortin-driven sexual function does not rely on metabolic neural circuits.

Increased fibrosis: A novel means by which GH influences white adipose tissue function.

OBJECTIVE: White adipose tissue (WAT) fibrosis - the buildup of extracellular matrix (ECM) proteins, primarily collagen - is now a recognized hallmark of tissue dysfunction and is increased with obesity and lipodystrophy. While growth hormone (GH) is known to increase collagen in several tissues, no previous research has addressed its effect on ECM in WAT. Thus, the purpose of this study is to determine if GH influences WAT fibrosis. DESIGN: This study examined WAT from four distinct strains of GH-altered mice (bGH and GHA transgenic mice as well as two tissue specific GH receptor gene disrupted lines, fat growth hormone receptor knockout or FaGHRKO and liver growth hormone receptor knockout or LiGHRKO mice). Collagen content and adipocyte size were studied in all cohorts and compared to littermate controls. In addition, mRNA expression of fibrosis-associated genes was assessed in one cohort (6month old male bovine GH transgenic and WT mice) and cultured 3T3-L1 adipocytes treated with GH. RESULTS: Collagen stained area was increased in WAT from bGH mice, was depot-dependent, and increased with age. Furthermore, increased collagen content was associated with decreased adipocyte size in all depots but more dramatic changes in the subcutaneous fat pad. Notably, the increase in collagen was not associated with an increase in collagen gene expression or other genes known to promote fibrosis in WAT, but collagen gene expression was increased with acute GH administration in 3T3-LI cells. In contrast, evaluation of 6month old GH antagonist (GHA) male mice showed significantly decreased collagen in the subcutaneous depot. Lastly, to assess if GH induced collagen deposition directly or indirectly (via IGF-1), fat (Fa) and liver (Li) specific GHRKO mice were evaluated. Decreased fibrosis in FaGHRKO and increased fibrosis in LiGHRKO mice suggest GH is primarily responsible for the alterations in collagen. CONCLUSIONS: Our results show that GH action is positively associated with an increase in WAT collagen content as well as a decrease in adipocyte size, particularly in the subcutaneous depot. This effect appears to be due to GH and not IGF-1 and reveals a novel means by which GH regulates WAT accumulation.

Growth hormone controls lipolysis by regulation of FSP27 expression.

Growth hormone (GH) has long been known to stimulate lipolysis and insulin resistance; however, the molecular mechanisms underlying these effects are unknown. In the present study, we demonstrate that GH acutely induces lipolysis in cultured adipocytes. This effect is secondary to the reduced expression of a negative regulator of lipolysis, fat-specific protein 27 (FSP27; aka Cidec) at both the mRNA and protein levels. These effects are mimicked in vivo as transgenic overexpression of GH leads to a reduction of FSP27 expression. Mechanistically, we show GH modulation of FSP27 expression is mediated through activation of both MEK/ERK- and STAT5-dependent intracellular signaling. These two molecular pathways interact to differentially manipulate peroxisome proliferator-activated receptor gamma activity (PPARγ) on the FSP27 promoter. Furthermore, overexpression of FSP27 is sufficient to fully suppress GH-induced lipolysis and insulin resistance in cultured adipocytes. Taken together, these data decipher a molecular mechanism by which GH acutely regulates lipolysis and insulin resistance in adipocytes.