SF1 Neurons: Comparison
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Please note this is a comparison between Version 1 by Rosalía Rodriguez Rodriguez and Version 2 by Dean Liu.

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. This neuronal population is therefore playing a critical role in hypothalamic regulation of diabetes and obesity.

  • SF1 neurons
  • ventromedial hypothalamus nucleus
  • obesity
  • diabetes
  • energy homeostasis
  • glucose homeostasis

1. Introduction

Obesity is a multifactorial chronic disease associated with a higher risk of developing cardiovascular diseases, diabetes, cancer, and, more recently, COVID-19 infection. According to the World Health Organization (WHO), in 2016, worldwide obesity had nearly tripled since 1975, with 39% of adults and 18% of children and adolescents overweight or obese [1]. The main metabolic comorbidity of obesity is type-2 diabetes that occurs when body tissues become resistant to insulin and is estimated to be the seventh leading cause of death [2]. Therefore, understanding the molecular and physiological mechanisms underlying the control of feeding behavior, energy balance and glucose homeostasis is crucial for the prevention and treatment of obesity and diabetes.

The regulation of peripheral metabolism and glucose homeostasis not only resides in the tissue The hypothalamus integrates multiple metabolic inputs from peripheral organs with afferent stimuli coming from other brain regions and coordinates a diversity of efferent responses to control food intake, fat metabolism, hormone secretion, body temperature, locomotion, and behavior in order to maintain energy balance and blood glucose levels. Within the hypothalamus, the ventromedial nucleus (VMH) located above the arcuate nucleus (ARC) and the median eminence, was identified in the mid-1900s as the satiety center because its injury produced hyperphagia, insulin resistance, and body weight gain [3][4][3,4]. At that point, VMH was demonstrated to play a key role in the control of energy expenditure and glucose homeostasis [3][5][3,5]. Since then, intensive research has been done on VMH and it is currently known that this hypothalamic area encompasses a heterogeneous set of neurons, which are differentiated by the genes they are expressing (Figure 1). Many of the genes highly expressed in the VMH have been identified and their functions have been explored (Figure 1) [6][7][8][6,7,8].

Interestingly, SF1 can suffer different post-translational modifications, which regulate its stability and transcriptional activity [9][14], but also control the expression of numerous downstream target genes, including CB1, BDNF, and Crhr2 [10][13]. Considering this, in order to explore the importance of SF1 neurons, transgenic mice lacking this nuclear receptor were studied by different researchers. However, when rescued from lethality by adrenal transplantation from WT littermates and corticosteroid injections, mutant mice displayed robust weight gain resulting from both hyperphagia and reduced energy expenditure [11][16]. These postnatal VMH-specific SF1 KO mice showed increased weight gain and impaired thermogenesis in response to a high-fat diet (HFD), being the first demonstration that the transcription factor SF1 is postnatally required in the VMH for normal energy homeostasis, especially under the HFD condition.

In an attempt to clarify the contribution of this specific population of neurons to hypothalamic regulation of obesity and diabetes, in the last 15 years, several transgenic models have been developed by deleting specific targets in SF1 neurons related to energy balance and glucose homeostasis. In 2013, a profound review article was published by Choi and colleagues [8] summarizing the last updates of SF1 neurons in energy homeostasis. Since then, new neuronal-based approaches (i.e., optogenetic and chemogenetic technology) and the generation of new transgenic mice in key target proteins have provided exciting insight into the implication of SF1 neurons on whole-body energy balance, particularly thermogenesis and glucose homeostasis, that are compiled in the present review.

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Figure 1. Schematic illustration of the pattern of genes highly expressed in the VMH. The majority of VMH cells, especially in the dorsomedial and central regions of VMH, express the nuclear receptor steroidogenic factor 1 (SF1). Leptin receptor (LEPR) positive cells mainly converge in the dorsomedial part, whereas insulin receptor (IR) maps the central region. Cells expressing brain-derived neurotrophic factor (BDNF) are mainly distributed in central and lateral areas of the VMH, estrogen receptor (ERα)-expressing cells are limited to the lateral region, and glucokinase (GK)-positive cells are present throughout the VMH. This schematic diagram is based on previous articles from Choi et al. [8] and Yi et al. [6].

2. Unraveling the Functions of SF1 Neurons in Energy Balance by Optogenetic and Chemogenetic Approaches

In order to selectively manipulate the SF1 neuronal activity in a physiological context, optogenetic and chemogenetic approaches have emerged [12][13][21,22]. These tools use channels that are activated by light and engineered G-protein coupled receptors controlled by exogenous molecules, respectively [12][13][21,22]. The incorporation of these approaches into animal models has greatly advanced our understanding of the SF1 role and neuronal circuits.

Mice engineered to activate SF1 neurons by optogenetics were designed through the injection of adeno-associated virus (AAV) particles expressing a Cre-dependent channelrhodopsin (ChRs) into the VMH of SF1-Cre mice to produce SF1-ChRs animals [14][15][23,24]. The advantage of this technology is the light-controllable activation of SF1 neurons in a spatiotemporal manner.

David J. Anderson and colleagues in 2015, demonstrated that the optogenetic stimulation of SF1 neurons applying a frequency of 20 Hz induced freezing or activity burst, while no response on feeding behavior or energy balance was reported [16][25]. Considering this information, two years later, other researchers showed that SF1 neurons exert a differential effect depending on the frequency of activation. They confirmed that high-frequency activation (>20 Hz) evokes a profound defensive response which includes freezing and escape attempts, but low-frequency activation (2 Hz) suppresses feeding after fasting and reduces the time that mice spend near to the food [15][24]. These novel results suggest that SF1 neurons dynamically modulate feeding and anxiety-related behaviors by changing the firing pattern and also indicate that this subset of hypothalamic neurons is involved in the fight or flight response.

These changes in fat mass could be explained by the SF1 modulation of fat oxidation. Very recently, it was established that SF1-hM3Dq mice increased energy expenditure and fat oxidation independent of the locomotion activity within 2-h post-activation [14][23]. Although this study did not evaluate the energy expenditure profile in SF1-hM4Di mice, it was expected that the inactivation of SF1 neurons reduced energy expenditure. Since TT prevents neurotransmitter release, SFTTmice displayed reduced energy expenditure and increased body weight [17][29].

Besides their implication in energy balance, the use of optogenetics has highlighted the role of SF1 neurons in the hypothalamic control of systemic glucose levels. For a long time, it was known that VMH triggered the counterregulatory response (CRR) induced by hypoglycemia [18][19][30,31] but it was not clear the contribution of SF1 neurons to this feedback response. In order to elucidate whether SF1 neurons are linked to this effect, an elegant experiment using optogenetic and chemogenetic tools was done by Gregory J Morton and colleagues, showing that selective inhibition of SF1 neurons blocked recovery from insulin-induced hypoglycemia. This evidence is concordant with those obtained from transgenic models such as mice lacking vesicular glutamate transporter 2 (VGLUT2) specifically in SF1 neurons since this genetic disruption attenuated recovery from insulin-induced hypoglycemia [20][33].

Taken all together, these genetic approaches have revealed the specific involvement of SF1 neurons in many aspects of metabolic regulation due to their direct or indirect role in the maintenance of the energy balance and glucose levels, confirming the classification of VMH as a primary satiety center [21][22][34,35].

3. Manipulation of Key Targets in SF1 Neurons: Lessons from Transgenic Mice

A particularly powerful strategy developed for the exploration of SF1 neurons in obesity and diabetes has been the design of the SF1 Cre mice. Several groups have generated different SF1 Cre transgenic lines in which the expression of Cre recombinase is derived bySf1regulatory elements [23][24][20,36]. These lines allow for ablating general factors or targets known to be associated with energy homeostasis by crossing them withfloxedstrains. In the following sub-sections, we discuss different studies of SF1-CRE transgenic mice organized by the type of molecular target under investigation (Table 1) as well as the sex-specific effect of SF1 neurons in energy balance.

Table 1. Genetic models developed to study SF1 neurons in energy balance.
]
[
60
]
M
HFD
↑
↑
n.s.
↑
-
↓
n.s.
↓
↓
Modulators of autophagy, mitochondrial and primary cilia function
Atfg7
Sf1-Cre; 
Atg7
loxP/loxP
M Fasting n.s. ↓ ↓ n.s. n.s. n.s. n.s. ↓ - [39][61]
UCP2 Ucp2KOKISf1 M Chow diet n.s. n.s. n.s. n.s. n.s. ↑ ↑ - - [40][62]
IFT88 IFT88-KOSF−1 M/F Chow diet ↑ n.s. ↓ ↑ ↑ ↓ ↓ ↓ ↓ [41][63]
      M/F HFD ↑ ↑ ↓ ↑ ↑ - - - -  
n.s.: No significant changes appreciated; -: not studied/unknown; M: male; F: female. SD: standard diet; HFD: high fat diet; HF-HS: high fat-high sucrose diet; BAT th.: brown fat thermogenesis.

Due to the importance of the anorectic hormone leptin in the central control of energy homeostasis, the physiological effects after deletion of leptin receptor (LEPR) in SF1 neurons have been thoroughly investigated. The first and most representative study was performed by Bradford Lowell and colleagues, in which genetic deletion of LEPR selectively from hypothalamic SF1 neurons triggered an increase in body weight gain without changes in food intake, leaving these mice unable to adapt to HFD or to activate energy expenditure [23][20]. Conversely to the deletion of LEPR, mice lackingSocs3showed improved weight-reducing effects of leptin, with a decrease in food intake and an enhanced energy expenditure under chow diet or HFD condition [25][37]. The importance of leptin signaling in energy balance through SF1 neurons was also reinforced by the specific deletion of the G protein α-subunit

The protein-tyrosine phosphatase 1B (PTP1B) is another negative regulator of leptin signaling in SF1 neurons (Figure 2). In vivo studies have demonstrated that whole-brain deletion of PTP1B resulted in leanness, hypersensitivity to leptin, and resistance to HFD-induced obesity, a phenotype partly associated with increased hypothalamic activation of STAT3 Surprisingly, its specific deletion in SF1 neurons resulted in increased adiposity in female mice exposed to HFD due to low energy expenditure, whereas leptin sensitivity was enhanced, and food intake was attenuated, findings that were likely explained by increased STAT3 activation [42][40]. Mice lacking PTP1B in SF1 neurons also had improved leptin and insulin signaling in VMH, suggesting that increased insulin responsiveness in SF1 neurons could overcome leptin hypersensitivity and promote adiposity [27][42][39,40].

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Figure 2. Leptin and insulin signaling in SF1 neurons. 

A more recent study tried to rescue native LEPR in SF1 neurons inLepR-deficient mice. They concluded that LEPR signaling in the VMH is not sufficient to protect against obesity in this null mouse [43][41]. This finding could explain that this neuronal population expressing LEPR works in conjunction with other types of neurons expressing the same receptor, and SF1 neurons by themselves cannot compensate for all receptor deficiency. Summing up, leptin signaling in SF1 neurons plays a key role in energy homeostasis regulation and mediates the proper physiological adaptation to HFD to avoid or delay the onset of obesity.

According to glucose metabolism, leptin has been long related to glucose homeostasis improving insulin sensitivity, since intra-VMH injection of leptin increases glucose uptake in peripheral tissues [44][42] and normalizes hyperglycemia [45][43]. The essential action of leptin in SF1 to correct diabetic hyperglycemia was clarified by further investigations. Particularly, in the specific knock—out ofSocs3in SF1 neurons, where leptin signaling is over-activated, Ren Zhang and colleagues observed improved glucose homeostasis, showing protection against hyperglycemia and hyperinsulinemia caused by HFD feeding [25][37]. Optogenetic activation of SF1 neurons has the same output as leptin increasing glucose uptake

It is known that insulin acutely suppresses food intake and decreases fat mass in both rodents and humans [46][47][45,46] Mice lacking insulin receptors (IR) in SF1 neurons did not show any differences in body weight when fed a chow diet but under HFD conditions, mutant mice were protected against obesity and showed an enhanced leptin sensitivity and glucose homeostasis [28][26]. Interestingly, exposure to HFD led to the overactivation of insulin in the VMH, leading to a reduction in SF1 neurons firing frequency, in comparison to the insulin resistance induced in ARC neurons. However, the specific contribution of insulin signaling in SF1 neurons and its relationship to peripheral insulin resistance and glucose levels needs further investigation.

Mice lacking p110α in SF1 neurons had reduced energy expenditure in response to hypercaloric feeding and, therefore, displayed an obesogenic phenotype. Mice lacking p110β in the same neuronal population had also decreased energy expenditure (reduced thermogenesis) leading to increased susceptibility to obesity, whereas, in contrast to the p110α subunit, p110β involved changes in peripheral insulin sensitivity [30][50]. In line with this evidence, deletion of FOXO1, a downstream transcription factor of insulin-PI3K (Figure 2), in SF1 neurons resulted in a lean phenotype with high energy expenditure, even in fasting, and these null mice presented an enhanced insulin sensitivity and glucose tolerance, in concordance with genetic deletion of IR in SF1neurons [31][51]. Although leptin and insulin can inhibit SF1 neurons using the same molecular cascade, they are anatomically segregated within the VMH (neurons expressing LEPR receptor are located in the VMHdm when depolarizing and scattered throughout the nucleus when hyperpolarizing, whereas those expressing IR are in the VMHc close to the ventricle)

Other hormones studied in SF1 neurons are estrogens. Female mice lacking the estrogenic receptor α (ERα) in SF1 neurons were obese due to a reduced energy expenditure [32][52]. Ablation of the ERα led to abdominal obesity with adipocyte hypertrophy in females, but not in male mice [48][53]. Despite the fact that most of the studies on SF1 neurons until now were performed only in male mice, these last results described, and others discussed later [42][35][40,54], reinforce the notion that SF1 neurons may have a sex-specific effect on energy balance and glucose metabolism.

Growth hormone (GH) also plays a role in glucose metabolism via SF1 neurons. GH is secreted in a metabolic stress situation such as hypoglycemia. Deletion of its receptor in SF1 neurons resulted in an impaired capacity for recovery from hypoglycemia [49][55]. This result supports the importance of SF1 neurons in the proper functionality of glucose homeostasis.

Altogether, these findings identify SF1 neurons (the predominant VMH population) as a key player in the regulation of energy expenditure and glucose homeostasis, being particularly important in the adaptive response to HFD feeding. Most of the mutant mice with deletion of several hormone receptors and associated proteins in SF1 neurons have no changes or mild metabolic alterations under chow diet, but they show substantial metabolic variations under HFD exposure. The action of hormones and related proteins in SF1 neurons is also involved in the CRR to hypoglycemia to maintain glucose balance between the brain and the periphery. Future studies are needed to describe the specific molecular mechanisms and subsets of SF1 neurons underlying the effects of hormones in glucose homeostasis and energy expenditure.

4. The Sex-Specific Effect of SF1 Neurons on Energy Balance

It is known that the VMH is sexually dimorphic, showing females higher ERα concentration than males [50][87]. Additionally, as described in Section 3, selective deletion of this receptor in SF1 neurons resulted in increased abdominal obese phenotype with adipocyte hypertrophy in females, but not in males [32][52]. Obesity in females was caused by decreased energy expenditure as they had reduced basal metabolic rate and impaired BAT thermogenesis [32][52]. It has been described also that estrogens regulate the activity of GI neurons of the ventrolateral portion of VMH, since females showed an attenuated response to hypoglycemia compared to male mice, although in this study it is not specified if these neurons were SF1 positive cells [51][88]. As has been already specified, there are other genetic deletions that presented different outputs in a sex-specific manner. Expression of mGluR5 in SF1 neurons was necessary for estradiol protective effects in glucose balance in female but not in male mice, and mGluR5 deletion resulted in reduced electrical activity only in female mice [35][54]. Deletion of α2δ-1 expression in SF1 neurons also presented sexually dimorphic effects depending on diet conditions. Particularly, female mice lacking α2δ-1 displayed glucose intolerance and insulin resistance under chow or HFD, as this phenotype much moderate in male mice [36][37][58,59]. Cheung et al. also observed sex-dependent changes when deleting VGLUT2 in SF1 neurons, since female but not male mice presented attenuation of DIO, and transgenic male mice showed behavioral changes not observed in female mice [52][89].
Estrogens could affect and change some intracellular signaling cascades leading to these differences observed between males and females, as female mice have greater expression of ERα. This would explain why the presence or absence of different patterns of receptors impacts the estrogenic effect on SF1 neurons, as some of the sex-specific signaling cascades are being altered. Other sex-specific effects related to SF1 neurons can be found in their synapses with POMC neurons, as estradiol attenuated the retrograde endocannabinoid signaling from POMC to SF1 neurons, increasing the glutamatergic inputs to POMC [53][78]. This study opens another possibility based on the fact hypothesis that estrogens do not interact directly with the specific SF1 neurons targeted in each study, but their effects fall on other cells acting on SF1 neurons.
Then, estrogen signaling in SF1 neurons is a must for metabolic health in female mice. Despite the fact that many studies presented in this review were performed only in male mice, these last results obtained in both sexes reinforce the idea of SF1 neurons having a sex-specific effect on energy balance and glucose metabolism.

5. Exploring the Neurocircuitry That Links SF1 Neurons to Other Brain Areas in Energy Balance

Remarkable progress in the neuroanatomy of VMH projections has been obtained from novel biological tools. Some notions on how the VMH connects with other brain centers come from stereotaxic injection with anterograde axonal tracers in adult rats [54][55][90,91]. While the results from these studies established that VMH is organized in subregions depending on their projection, the inherent limitations of this method make it difficult to assess the specific neuronal network involved in SF1 neurons. To overcome these limitations, Sf-1TauGFP and Z/EGSf1:Cre mice models were originally designed to trace the major VMH axonal projections during embryonic and postnatal stages [56][9].
The first of these models is a knock-in line that contains the wheat germ agglutinin (WGA) and Tau-green fluorescent protein (TauGFP) under the control of Sf-1 regulatory elements. In the second model, the SF1 Cre mouse was crossed with a Z/EG reporter mouse, resulting in constitutive expression of eGFP (enhanced GFP) after Cre-mediated recombination [56][9]. The analysis of the results obtained from both models indicated the efferent SF1 projection in ascending and descending tracts that innervate different structures such as the hypothalamus, thalamus, the basal forebrain, and the brainstem. Interestingly, SF1 projections targeting the general vicinity of gonadotropin-releasing hormone (GnRH) neurons suggest the potential role in fertility physiology [56][9].
As expected, experiments using these models showed that SF1 neurons projected to areas implicated in body weight regulation, including the paraventricular nucleus of the hypothalamus (PVN) [56][57][9,92]. However, it was not possible to detect any GFP+ fibers within the ARC. Thus, additional studies using synaptophysin or rabies virus would be helpful to explore the specific network between SF1 and hypothalamic nuclei involved in energy balance. Recently, Yunglei Yang and colleagues have optogenetically identified the downstream target underlying the SF1 suppression of food intake (Figure 5). The authors used the SF1 ChR2 mice, but the fiber optic cannula was implanted above the PVN, therefore the photostimulation of this area would only activate the SF1-PVN projections. They showed that high-frequency stimulation of this circuit potently reduced food intake even in 24 h food-deprived mice [14][23].
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Figure 5. Neurocircuitry linking SF1 VMH neurons to other brain areas in energy balance.
Downstream projections of SF1 neurons regulating glycemia were identified through the same novel strategy derived from optogenetics. The researchers administrated fluorescently tagged ChRs into the VMH of SF1-Cre mice to visualize the projection fields using histological imaging to detect the EYFP reporter in axonal projections [58][32]. Once identified this target site, a fiber optic was implanted to depolarize the final projection by laser stimulation. With this strategy, it was possible to demonstrate that VMHSF1→aBNST is the most relevant circuit involved in controlling glycemia since the photostimulation of this circuit triggered an increase of the blood glucose levels [58][32] (Figure 5). Interestingly, other functions have been attributed to this specific circuit: Fan Yang and colleagues recently demonstrated that SF1 neurons are innervated by upstream BNST neurons and send projections to the NST nucleus to regulate anxiety-like behavior and bone metabolism [59][93] (Figure 5).
The use of current and novel biological tools provides several clues about the neurocircuits regulating blood glucose and energy balance, and the afferent and efferent connections linking SF1 neurons with other neuronal populations. An improving understanding of the functional organization of SF1 neurons may help to identify future strategies for metabolic diseases such as obesity and diabetes.

6. Concluding Remarks and Future Perspectives

In the last years, the critical role played by the hypothalamus in the regulation of energy balance and glucose homeostasis has gained substantial importance. However, the exact mechanisms and neuronal circuits underlying this regulation and the pathogenesis of obesity and insulin resistance remain poorly understood. The growing literature is demonstrating that the origin of these diseases is beyond feeding and pancreatic insulin secretion, and needs further definition. Here we extensively review that SF1 neurons in the hypothalamus provide a “central role” in the control of blood glucose levels, insulin sensitivity in peripheral tissues, adipose tissue plasticity, and thermogenesis activation. SF1 neurons 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. Interestingly, transgenic mice lacking different targets in SF1 neurons show an altered metabolic phenotype mostly under HFD feeding, but not under chow diet, indicating that SF1 neurons are particularly important for metabolic adaptation in the early stages of obesity. These investigations also demonstrate the sex-specific effects of SF1 neurons in the VMH, and the importance of the analysis of the phenotype in both male and female mice when exploring energy balance and metabolism in transgenic models.
Although optogenetic and chemogenetic tools have clearly demonstrated SF1 function in glucose homeostasis, adiposity, and energy expenditure, there are still contradictory results in these functions after deletion of specific receptors in SF1 neurons (e.g., mGluR5). These controversies could be associated with the existence of several sub-populations of SF1 neurons that respond differently to insulin, leptin, and glucose. For instance, whereas some SF1 neurons seem to be specialized in the regulation of blood glucose levels, some others are responsible for insulin sensitivity in the periphery.
When investigating the hypothalamic regulation of obesity and diabetes, in addition to the identification of SF1 sub-populations, it is important to explore the coordination of SF1 neurons with other neurons outside the VMH to trigger metabolic functions. For instance, HFD-induced hyperinsulinemia drives SF1 neurons hyperpolarization, leading in turn to functional changes in the synaptic output onto POMC neurons, causing obesity and glucose intolerance. This evidence suggests that the nucleus-specific responses upon HFD feeding can cooperate to cause obesity and diabetes, and disruption of this cooperation could act as a link between both diseases.
Despite the advances in the neurocircuitry connecting SF1 VMH neurons with other brain areas, the exact efferent circuits leading to changes in peripheral tissues need further investigation. How mice lacking a protein only in SF1 neurons present a strong phenotype in the periphery in terms of glucose homeostasis and energy expenditure under nutritional challenges? Are these circuits restricted to SNS and PSNS? A new point of view also emerges from these studies: a disruption in a specific type of neurons in the hypothalamus could trigger the pathogenesis of type 2 diabetes and obesity. How this neuronal dysfunction drives peripheral insulin resistance, adiposity, and thermogenesis alteration remains unclear. Reconsidering the pathogenesis of obesity and type 2 diabetes and now including the essential role of SF1 neurons, new strategies to treat these diseases could emerge. Targeting this specific population of neurons in the VMH, and even another cooperating population outside the VMH at the same time could modulate specific metabolic functions, a challenging approach but with significant translational impacts in the management of obesity and diabetes.
 

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Type of Target Target Mice Model Name Sex Challenge BW FI EE Adiposity Glycemia Glucose Tolerance Insulin

Sensitivity		 Leptin Sensitivity SNS Activity Ref.
Hormone receptors and related signaling pathways LEPR Sf1-Cre, Leprflox/flox M SD ↑ n.s. n.s. ↑ n.s. - - - - [23][20]
HFD ↑ ↑ ↓ ↑ n.s. - - - -
SOCS3 Sf1-Cre, Socs3flox/flox M SD n.s. ↓ ↓ - ↓ ↑ ↑ ↑ - [25][37]
HF-HS n.s. ↓ ↓ - ↓ ↑ ↑ ↑ -
Leptin (a) ↓ ↓ - - - - - ↑ -
Gsα VMHGsKO M (b) SD n.s. n.s. n.s. - n.s. n.s. n.s. n.s. - [26][38]
HFD n.s. n.s. n.s. - ↓ ↑ ↑ ↑ -
PTP1B Sf1-Ptpn1−/− F HFD ↑ ↓ ↓ ↑ - - ↑ ↑ ↓ [27][39]
M HFD n.s. - - n.s. - - - - -
IR SF-1ΔIR   SD n.s. n.s. n.s. n.s. - - - - - [28][26]
      HFD ↓ ↓ n.s. ↓ n.s. ↑ ↑ ↑ -  
p110α p110αlox/lox/SF1-Cre M SD n.s. n.s. n.s. n.s. n.s. - n.s. ↓ - [29][49]
HFD ↑ n.s. ↓ ↑ - - - - -
p110β p110β KOsf1 M SD n.s. n.s. ↓ BAT th.(c) n.s. n.s. ↓ ↓ - - [30][50]
  HFD ↑ n.s. ↓ ↑ ↑ - - - -
FOXO1 Foxo1 KOSf1 M SD ↓ n.s. ↑ ↓ - - - - - [31][51]
F SD ↓ n.s. ↑ ↓ - - - - -
M HFD ↓ n.s. ↑ ↓ ↓ ↑ ↑ ↑ -
ERα ERαlox/lox/SF1-Cre F SD ↑ n.s. ↓ ↑ n.s. ↓ - - - [32][52]
F HFD ↑ n.s. ↓ ↑ - - - - ↓
Nutrient sensors AMPK SF1-Cre AMPKα1flox/flox M SD ↓ n.s. ↑ ↓ - - - - ↑ (d) [33][56]
M HFD ↓ n.s. ↑ ↓ ↓ ↑ n.s. - -  
SIRT1 Sf1-Cre; Sirt1loxP/loxP M/F SD n.s. n.s. n.s. n.s. n.s. - - - - [34][57]
HFD ↑ n.s. ↓ ↑ ↑ ↓ ↓ ↓ -
Glutamatergic neurotransmission and synaptic receptors VGLUT2 Sf1-Cre; Vglut2flox/flox M/F SD n.s. - - - ↓ - - - - [20][33]
M/F HFD ↑ ↑ n.s. ↑ - - - - -  
mGluR5 mGluR52L/2L:SF1-Cre F SD n.s. n.s. n.s. - n.s. ↓ ↓ - ↓ [35][54]
M SD n.s. n.s. n.s. - n.s. n.s. n.s. n.s. n.s.
M/F HFD n.s. n.s. n.s. - - - - - -
α2δ-1 α2δ-12L/2L:SF1-Cre M SD n.s. n.s. n.s. n.s. n.s. ↓ ↓ - ↓ [36][37][58,59]
M HFD n.s. n.s. n.s. n.s. n.s. n.s. n.s. - -
F SD n.s. n.s. n.s. n.s.   ↓ ↓ - -
F HFD ↑ n.s. n.s. n.s. n.s. ↓ ↓ - ↑
CB1 SF1-CB1-KO M SD n.s. n.s. ↑ BAT th. ↓ n.s. ↑ ↑ ↑ ↑ [38
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