Altered cross-talk between the hypothalamus and non-homeostatic regions linked to obesity and difficulty to lose weight

Interactions between the hypothalamus and non-homeostatic regions may contribute to explain the difficulty to lose weight in obesity, an assumption never tested in human longitudinal studies. We investigated whether the functional connectivity between the medial and lateral hypothalamus (MH and LH) and corticostriatal regions differs between individuals with excess weight (n = 42) and normal weight (n = 39) using a seed-based resting-state approach. In addition, we examined the longitudinal association between functional connectivity and weight loss in a 3-month follow-up diet. Results showed that participants with excess weight had increased connectivity between the MH and the striatum and subgenual anterior cingulate cortex, and decreased connectivity with the middle frontal gyrus, and the bed nucleus of the stria terminalis (BNST), as well as a decreased connectivity between the LH and the cerebellum. Decreased connectivity between the MH and the posterior part of the BNST, and between the LH and the cerebellar cortex, predicted a greater percentage of weight loss. Functional connectivity measures explained 36% of the 3-month weight change among individuals with excess weight. We conclude that altered functional connectivity between homeostatic-hypothalamic regions and non-homeostatic corticostriatal and cerebellar regions is linked to obesity and difficulty to lose weight.

. Correlations between the functional connectivity of the medial (MH) and lateral (LH) hypothalamic seeds and the percentage of weight change for normal and excess weight and participants and between-group interactions. Coordinates (x, y, z) are given in Montreal Neurological Institute (MNI) Atlas space. Signs (+) and (-) refer to the direction of the significant correlations. Text in italics refers to the between-group connectivity correlates that map on the betweengroup differences. All results surpassed a height threshold of p<0.001. For within-group correlation effects a cluster of 232 mm3 (29 voxels) for the MH, and 1072 mm3 (134 voxels) for the LH was used, explored inside the mask of within-group effects. For the between-group correlation effects, a cluster of 80 mm3 (10 voxels) was used both for the MH and the LH, explored inside the mask of between-group effects for each seed, respectively.

Verification of the Medial and Lateral Hypothalamic Functional Connectivity Maps
The MH positive connectivity map predominantly included ventral regions such as the operculum orbitalis and the amygdalae bilaterally, and a cluster comprising the hippocampi that extended to the dorsal superficial thalamic nuclei, the superior temporal gryus and the fusiform gyrus. Distinctly, the LH positive connectivity map largely included frontal cortices such as the dorsomedial prefrontal cortex, rostral sections of the anterior cingulate cortex and the inferior frontal gyri extending to the operculum opercularis, and a cluster comprising the bed nucleus of the stria terminalis, striatal nuclei, and anterior and middle portions of the insulae (see also Fig. S1).
The negative functional connectivity maps of the MH and LH were also highly distinct and they highly contained those brain regions positively associated with the other seed (i.e. brain regions showing a positive connectivity with MH, showed a negative connectivity with LH, and viceversa). In that way, the MH negative connectivity map predominantly included frontal cortices (e.g. middle and inferior frontal gyri, rostral anterior cingulate cortex, operculum opercularis), striatal regions and the bed nucleus of the stria terminalis, whereas the LH negative connectivity map included the amygdalahippocampus complex, and superior temporal and fusiform gyri (see also Fig. S1).

Within-group correlations with percentage of weight change
Normal weight: In normal weight participants, weight loss was associated with an increased functional connectivity between the MH seed and the right posterolateral orbitofrontal cortex, and with a decreased connectivity between the LH and the posterior cingulate cortex (see also Table S2).
Excess weight: In excess weight participants, weight loss was associated with a decreased functional connectivity between the MH seed and the BNST, as well as with a decreased connectivity between the LH seed and the left amygdala-hippocampus complex, and the right anterior insula (see also Table S2). Additionally, in these participants weight loss was associated with an increased connectivity between the MH seed and the right amygdala.

Multiple Regression Analyses
Data met all assumptions required for multiple regression analysis. An analysis of standard residuals was carried out, which showed that the data contained no outliers (std. residuals min = -1.75, std. residuals max = 1.70). Tests to see if the data met the assumption of collinearity indicated that multicollinearity was not a concern (MH-pBNST, tolerance = 0.99, VIF = 1.002; LH-cerebellum, tolerance = 0.99, VIF = 1.002).
The data met the assumption of independent errors (Durbin -Watson value= 1.61). The histograms of standardized residuals indicated that the data contained approximately normally distributed errors, as did the normal P-P plots of standardized residuals, which showed points that were not completely on the line, but close. The scatterplot of standardized predicted values showed that the data met the assumptions of homogeneity of variance and linearity. Finally, the data also met the assumptions of non-zero variances (% weight change, variance = 15.369; MH-pBNST, variance = 0.923; LHcerebellum, variance = 0.923). and negative (-) associations with % weight change in normal and excess weight subjects. The right hemisphere corresponds to the right side of axial and coronal views.
The color bar indicates t-values.
Supplementary Table S1. Within-group positive and negative functional connectivity maps for the medial (MH) and the lateral (LH) hypothalamic seeds.
Coordinates (x, y, z) are given in Montreal Neurological Institute (MNI) Atlas space.
Ns, indicates non-significant clusters. All results herein surpassed a height threshold of p<0.001 and 992 mm 3 (124 voxels).