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Insulin and Brain Reward Systems
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Brian C. Liu, Qingchen Zhang, Emmanuel N. Pothos
Leptin is a hormone that is important for regulating metabolism and inhibiting food intake while it significantly impacts central pathways coding for food and drug reward. Mutations in leptin and in the leptin receptor cause hyperphagia and obesity (52, 53). When leptin receptors expressed on POMC neurons were knocked out in mice, the mice were obese and had an abnormal expression of neuropeptides within the hypothalamus (54). In rodents with mutated leptin receptors, reactivation of these leptin receptors in the arcuate resulted in smaller improvements in body weight, but significant improvements in the level of blood glucose and hyperinsulinemia (55–57). At the same time, leptin receptors are expressed on VTA dopamine cell bodies and leptin-deficient mice exhibit not only obesity but also significant deficits in central dopamine exocytosis (58). All of this evidence suggests that hypothalamic arcuate POMC neurons are essential in the pathway for regulating glucose homeostasis via leptin, while the role of leptin and insulin in modulating reward pathways appears to be synergistic at the very least.
Bardet−Biedl Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Obesity is characterized by the disproportionate distribution of adipose tissue on the abdomen and chest (so-called “truncal obesity’) rather than the arms and legs, producing an apple-shape body type (with mean body mass index of 31.5 mg/m2 in females and 36.6 mg/m2 in males). Emerging in 90% of patients from the first year of life, obesity becomes most prominent in the trunk and proximal limbs in adulthood. Factors contributing to the development of obesity may include (i) deregulation of appetite, (ii) altered leptin resistance, (iii) altered neuroendocrine signaling from ciliated neurons to fat storage tissues, (iv) impaired leptin receptor signaling, (v) reduced number of cilia due to BBS gene mutations and alteration in the sonic hedgehog (Shh) and Wnt signaling pathway in the differentiating preadipocytes [24]. At the molecular level, BBS4 (rs7178130) and BBS6 (rs6108572 and rs221667) are linked to early-onset childhood obesity and common adult morbidity, while BBS2 (rs4784675) is associated with common adult obesity.
Genetics, Epigenetics, and Microbiome
Published in Emily Crews Splane, Neil E. Rowland, Anaya Mitra, Psychology of Eating, 2019
Emily Crews Splane, Neil E. Rowland, Anaya Mitra
Are there examples of leptin-related mutations and obesity in humans? Yes, but they are quite rare. Montague et al. (1997) identified three very obese children who had undetectable blood levels of leptin; the obesity exhibited by these children was reversed by chronic treatment with synthetic leptin. Mutations to the leptin receptor are slightly more common, occurring in up to 3% of early-onset severe obesity. Individuals with these mutations, much like the mice, have normal birth weights but start to gain weight abnormally fast within the first few months of life. They show increased food seeking and overeating at least into adolescence (for a review, see Ramachandrappa & Farooqi, 2011).
The Postnatal Leptin Surge Supports Immune Cell Function in Rats
Published in Immunological Investigations, 2022
Caroline Hunsche, Oskarina Hernandez, Virginia Mela, M. Paz Viveros, Mónica De la Fuente
In the present study, male and female rats were treated with the pegylated super rat leptin antagonist (D23L/L39/D40A/F41A muteins). These muteins act as potent antagonists and are capable of switching-off the endogenous leptin. They have a similar affinity than non-mutant leptin for binding to the leptin receptor with the advantage of lacking their biological activity. The antagonists are monopegylated at N terminus to prolong and enhance their in-vivo activity (Mak et al. 2018; Niv-Spector et al. 2012; Salomon et al. 2006). In the current study, the leptin antagonist was administrated in male and female rats from PND5 to 9 coinciding with the neonatal leptin surge in mice and rats (Ahima et al. 1998; Delahaye et al. 2008). The animals treated with this antagonist displayed a significant impairment of chemotactic capacity, anti-tumor NK activity and proliferation of lymphocytes in response to mitogens (LPS and ConA). Moreover, leukocyte cell cultures under ConA and LPS-stimulated conditions showed an impaired release of cytokines in those rats treated with the leptin antagonist. We chose the spleen of these animals to carry out the study since this secondary lymphoid organ, which is the largest in both humans and rodents, is responsible for establishing effective innate and adaptive immune responses and regulating cytokine production (Cesta 2006; Huston et al. 2006; Nolte et al. 2002).
The modulatory effects of irisin on asprosin, leptin, glucose levels and lipid profile in healthy and obese male and female rats
Published in Archives of Physiology and Biochemistry, 2022
Sibel Ozcan, Nazife Ulker, Ozgur Bulmus, Ahmet Yardimci, Mete Ozcan, Sinan Canpolat
Recently, the etiopathological studies on obesity have focussed on several hormones (appetite hormones, an/orexigenic peptide), which play a role in metabolism and body fat distribution (van der Klaauw 2018). There is a correlation between the aetiology of obesity and appetite hormones through stimulation of hunger/satiety signals, acting on fat metabolism or glucose homeostasis or inhibiting/adjusting appetite (Mantzoros et al. 2011). Irisin infusion could alter the hunger/satiety hormone levels (Tekin et al.2017). Leptin is predominantly secreted by adipose tissue and regulates energy balance. Although leptin reduces appetite, obese individuals with high circulating leptin levels were suggested to have resistance to leptin (Ozata et al.1999). Leptin resistance could alter leptin receptor signalling (Myers et al.2008). Exercise prevents against high-fat diet-induced leptin resistance in obesity (Carhuatanta et al.2011).
Mechanistically acting anti-obesity compositions/formulations of natural origin: a patent review (2010–2021)
Published in Expert Opinion on Therapeutic Patents, 2022
Pracheta Sengupta, Niyati Tiwari, Tanya Bhatt, Atish T. Paul
The nucleus of the hypothalamus can also be directly influenced by circulating factors as it is partially outside the blood–brain barrier. There are two well-characterized neuronal populations involved in this pathway, namely, appetite inhibiting and appetite-stimulating neurons. The appetite inhibiting neurons further includes proopiomelanocortin (POMC) & cocaine and amphetamine-regulated transcript (CART) co-expressing neurons. Appetite-stimulating neurons includes neuropeptide Y (NPY) and agouti-related peptide co-expressing neurons [24–26]. One of the major genes associated with anorexigenic signaling is the melanocortin receptor genes (MC2R, MC3R, and MC4R) that stimulates melanocortin stimulating hormone (MSH) and melanin-concentrating hormone (MCH) [27]. In the hypothalamus, the neurotransmitter α-melanocyte stimulating hormone (α-MSH) is produced that act on the melanocortin receptor in another part of the hypothalamus to reduce food intake. Lack of leptin on the leptin receptor, in both animals and humans, leads to obesity (Figure 1(C)).