New Insights of SF1 Neurons in Hypothalamic Regulation of Obesity and Diabetes

Abstract

Despite the substantial role played by the hypothalamus in the regulation of energy balance and glucose homeostasis, the exact mechanisms and neuronal circuits underlying this regulation remain poorly understood. In the last 15 years, investigations using transgenic models, optogenetic, and chemogenetic approaches have revealed that SF1 neurons in the ventromedial hypothalamus are a specific lead in the brain’s ability to sense glucose levels and conduct insulin and leptin signaling in energy expenditure and glucose homeostasis, with minor feeding control. Deletion of hormonal receptors, nutritional sensors, or synaptic receptors in SF1 neurons triggers metabolic alterations mostly appreciated under high-fat feeding, indicating that SF1 neurons are particularly important for metabolic adaptation in the early stages of obesity. Although these studies have provided exciting insight into the implications of hypothalamic SF1 neurons on whole-body energy homeostasis, new questions have arisen from these results. Particularly, the existence of neuronal sub-populations of SF1 neurons and the intricate neurocircuitry linking these neurons with other nuclei and with the periphery. In this review, we address the most relevant studies carried out in SF1 neurons to date, to provide a global view of the central role played by these neurons in the pathogenesis of obesity and diabetes.

Hypothalamic endocannabinoids in obesity: an old story with new challenges

“…They reported that hypothalamic POMC neurons were modulated by sex hormones, as estradiol in post-synaptic POMC impaired CB1 receptor signaling at glutamatergic pre-synaptic terminals led to a reduction in food intake, whereas testosterone had the opposite effect [ 111 , 112 ]. More recently, the same authors reported that SF1 neurons of the VMH furnish sexually differentiated endocannabinoid- and diet-sensitive glutamatergic inputs to ARC/POMC neurons that would suggest a basis for sex differences in cannabinoid regulation for energy homeostasis [ 113 , 114 ]. For electrophysiological recordings in hypothalamic slices from intact and castrated guinea pigs, and in vitro optogenetic experiments in intact male and ovariectomized female SF1-Cre mice, the following specific findings were reported: (1) testosterone increased endocannabinoid tone at SF1/POMC synapses by increasing intracellular calcium; (2) endocannabinoid-mediated retrograde inhibition of glutamatergic input at SF1/POMC synapses was sexually differentiated and negatively regulated by estradiol; and (3) HFD feeding had a substantial impact on sex differences in endocannabinoid-induced regulation of energy homeostasis.…”

The ventromedial hypothalamic nucleus: watchdog of whole-body glucose homeostasis

“…Recently, Fosch and colleagues have summarized key molecules or targets implicated into glucose homeostasis and/or energy balance in the VMH based on SF1-Cre transgenic mice (for the review see Ref. [ 129 ]). In addition, most recent studies suggested that Rap1 and prostaglandin in the VMH have also been implicated into glucose homeostasis [ 123 , 128 ].…”

Hypothalamic Regulation of Obesity

“…Evidence has also highlighted the participation of non-neuronal populations (i.e., microglia and astrocytes), and even the interesting cross-talk between these types of brain cells, whose disruption leads to insulin resistance and obesity. In this Special Issue, we report on the most recent insights into the hypothalamic circuitries and pathways involving neurons [3][4][5][6][7], astrocytes [8,9], and microglia [10,11] in obesity development and associated complications. The emerging contribution of astrocyte-neuron [9] and microglia-neuron cross-talks [12] in the hypothalamus and the contribution of microbiota and the gut-brain axis controlling food intake and energy homeostasis [13] are also presented in this Special Issue (Figure 1).…”

“…For instance, lacking SIRT1 or SIRT6 in POMC neurons affects energy expenditure and adiposity; however, SIRT1 in AgRP neurons specifically affects eating behavior, and in oxytocin neurons in the PVN controls diet preference. In addition to sirtuins, Fosch et al [4] provide new insights into other targets in SF1 neurons of the ventromedial hypothalamus that play a critical role not only in body weight control and adiposity, but also in glucose tolerance and insulin and leptin sensitivity, with minimal effects on food intake and differential actions between male and female mice. The authors also report how nutrient sensors such as AMPK and SIRT1, glutamatergic transmission, synaptic receptors, and mediators of autophagy in SF1 neurons are promising therapeutic targets against obesity and diabetes, reinforcing the "central role" of the hypothalamus in the control of peripheral metabolism beyond the regulation of feeding behavior [4].…”

“…In addition to sirtuins, Fosch et al [4] provide new insights into other targets in SF1 neurons of the ventromedial hypothalamus that play a critical role not only in body weight control and adiposity, but also in glucose tolerance and insulin and leptin sensitivity, with minimal effects on food intake and differential actions between male and female mice. The authors also report how nutrient sensors such as AMPK and SIRT1, glutamatergic transmission, synaptic receptors, and mediators of autophagy in SF1 neurons are promising therapeutic targets against obesity and diabetes, reinforcing the "central role" of the hypothalamus in the control of peripheral metabolism beyond the regulation of feeding behavior [4]. In this sense, Fukumura et al [5] found new evidence in this special issue about the effects of a novel hypothalamic small protein, named neurosecretory protein GL (NPGL), on glucose and insulin homeostasis.…”