Sex difference in physical activity, energy expenditure and obesity driven by a subpopulation of hypothalamic POMC neurons

Abstract

ObjectiveObesity is one of the primary healthcare challenges of the 21st century. Signals relaying information regarding energy needs are integrated within the brain to influence body weight. Central among these integration nodes are the brain pro-opiomelanocortin (POMC) peptides, perturbations of which disrupt energy balance and promote severe obesity. However, POMC neurons are neurochemically diverse and the crucial source of POMC peptides that regulate energy homeostasis and body weight remains to be fully clarified.MethodsGiven that a 5-hydroxytryptamine 2c receptor (5-HT2CR) agonist is a current obesity medication and 5-HT2CR agonist's effects on appetite are primarily mediated via POMC neurons, we hypothesized that a critical source of POMC regulating food intake and body weight is specifically synthesized in cells containing 5-HT2CRs. To exclusively manipulate Pomc synthesis only within 5-HT2CR containing cells, we generated a novel 5-HT2CRCRE mouse line and intercrossed it with Cre recombinase-dependent and hypothalamic specific reactivatable PomcNEO mice to restrict Pomc synthesis to the subset of hypothalamic cells containing 5-HT2CRs. This provided a means to clarify the specific contribution of a defined subgroup of POMC peptides in energy balance and body weight.ResultsHere we transform genetically programed obese and hyperinsulinemic male mice lacking hypothalamic Pomc with increased appetite, reduced physical activity and compromised brown adipose tissue (BAT) into lean, healthy mice via targeted restoration of Pomc function only within 5-HT2CR expressing cells. Remarkably, the same metabolic transformation does not occur in females, who despite corrected feeding behavior and normalized insulin levels remain physically inactive, have lower energy expenditure, compromised BAT and develop obesity.ConclusionsThese data provide support for the functional heterogeneity of hypothalamic POMC neurons, revealing that Pomc expression within 5-HT2CR expressing neurons is sufficient to regulate energy intake and insulin sensitivity in male and female mice. However, an unexpected sex difference in the function of this subset of POMC neurons was identified with regard to energy expenditure. We reveal that a large sex difference in physical activity, energy expenditure and the development of obesity is driven by this subpopulation, which constitutes approximately 40% of all POMC neurons in the hypothalamic arcuate nucleus. This may have broad implications for strategies utilized to combat obesity, which at present largely ignore the sex of the obese individual.

Serotonin engages an anxiety and fear-promoting circuit in the extended amygdala

“…Sert Cre mice (from GENSAT) were a generous gift from Dr. Bryan Roth. Htr2c Cre mice were supplied by Dr. Lora Heisler and are described in detail elsewhere7.…”

“…These results indicate that 5-HT DRN→BNST projections have a predominantly excitatory effect that is dependent on 5-HT 2C R signaling. To examine the role of 5-HT 2C R containing neurons in anxiety-like behavior, we next took advantage of a Htr2c Cre mouse line (Extended Data Figure 3a-b)7. Using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)8, we found that activation of G q signaling in 5-HT 2C R-expressing neurons in the BNST significantly delayed the onset of feeding in the NSF assay without impacting home cage feeding behavior (Extended Data Figure 3c-g), thus phenocopying the effect observed with 5-HT DRN→BNST fiber stimulation during NSF.…”

Obesity in Low- and Middle-Income Countries: Burden, Drivers, and Emerging Challenges

“…Higher obesity among women compared with men in LMICs could be driven by several factors, including sex differences in physiological responses to early-life nutrition, pregnancy-associated weight gain combined with higher parity (40), hormonal signaling related to energy expenditure (16), physical activity levels (144), alcohol consumption (137), depression (79), past and present economic circumstances (19), and sociocultural factors such as the perception of ideal body size and beliefs surrounding acceptability of physical activity in some contexts (68,94). Because maternal obesity is a risk factor for childhood obesity, the increasing obesity prevalence among women of reproductive age could have important intergenerational effects in LMICs (20).…”

Activation of Ventral Tegmental Area 5-HT2C Receptors Reduces Incentive Motivation

“…Next, we characterized the neurons expressing 5-HT 2C Rs within the VTA and their response to lorcaserin as measured by c-fos immunoreactivity (IR). To investigate the role of VTA 5-HT 2C receptor expressing neurons in the modulation of appetite and the food motivated behavior, we employed a chemogenetic approach (designer receptors exclusively activated by a designer drug, DREADD) (Urban and Roth, 2015) to acutely activate or inhibit this population of neurons using a recently developed 5-HT 2C R CRE mouse line (Burke et al , 2016). These studies identify the therapeutic potential of the activation of a small subset of 5-HT 2C receptor expressing neurons in the reduction of homeostatic feeding and also more broadly in incentive motivation.…”