**3. Function**

### *3.1. Resting State*

It is well established that sex/gender differences exist in human brain functional connectivity [39,40]. Elevated BMI, the most common marker of obesity (BMI > 30 kg/m2), has also been associated with brain connectivity [41,42]. However, the interaction between sex/gender and obesity remains unclear. Resting state connectivity in functional magnetic resonance imaging (fMRI) is an important but understudied area as it pertains to sex/gender differences in obesity. Few studies by one group of researchers [43–45] provide a preliminary understanding of the effects of sex/gender and BMI on brain connectivity, though these results, to our knowledge, have yet to be replicated by others. These results are illustrated in Figure 2 and outlined in Table 2.

**Figure 2.** Resting state connectivity differences in obesity by sex/gender. Red circles indicate changes among females and blue circles indicate changes among males. Arrows indicate the direction of the correlation between centrality and obesity metrics (i.e., BMI, total body fat, serum leptin, Yale Food Addiction Scale (YFAS) score). VTA: ventral tegmental area.

There are many methodological approaches to examine resting state fMRI signals, but existing studies have focused on network centrality and slow-wave connectivity. Centrality generally assesses the connectedness of a given brain region to many others [46]. Gupta et al. (2017) found that women with obesity have higher centrality measures in several regions of the reward network, including the left amygdala, right NAcc, and bilateral hippocampus, than men with obesity, while men have higher centrality measures in the bilateral putamen [43]. Measures of food addiction also seem to contribute to the centrality of reward regions among women; scores on the Yale Food Addiction Scale, a standardized and widely used metric to quantify food addiction, were positively associated with the centrality of the ventral tegmental area (VTA) among women whereas they were negatively associated among men [45,47]. While men with obesity have lower centrality in reward regions than their female counterparts, Gupta et al. (2017) demonstrated that men with obesity have greater centrality in the right putamen, hippocampus, and medial orbitofrontal gyrus relative to lean men, and women with obesity have greater centrality in the left amygdala than lean women [43]. Thus, alterations in the centrality of the reward network tend to occur in a sex/gender-dependent manner, with female individuals showing greater centrality than their male counterparts. However, the interaction between sex/gender and obesity on brain network centrality has yet to be formally tested, so it remains unclear.



Obesity also shows a correlation with slow-wave connectivity throughout the reward network in a sex/gender-dependent manner. Another study by Gupta et al. (2018) examined two classes of slow-wave neural signals, labelled slow-4 and slow-5, in obese and lean men and women [44]. The slow-4 signal (medium frequency) is thought to arise from the basal ganglia, while the slow-5 signal (low frequency) is thought to arise from the cortex [48]. The slow-4 signal in the right globus pallidus and bilateral putamen was associated with BMI in females but not in males [44]. Further, among females, higher BMI was associated with lower slow-5 connectivity between the left globus pallidus and substantia nigra with the bilateral posterior mid cingulate cortex and frontal cortical regions [44]. This finding is reminiscent of the aberrant cortico-striatal signaling characteristic of obesity and substance use disorders [12,44]. Conversely, among males, greater BMI was associated with higher left globus pallidus and substantia nigra slow-5 connectivity with the medial frontal cortex [44]. Centrality measures have corroborated these findings; in women, higher food addiction scores were associated with lower centrality in frontal areas and higher centrality in VTA and this pattern is reversed in men [45]. This further suggests that neuroadaptations in reward regions appear to play a larger role in compulsive eating in women than for men.
